Chemical ablation and method of treatment for various diseases

ABSTRACT

Embodiments of the present invention provide a device and a method for treating at least one of hypertension, pulmonary arteries, diabetes, obesity, heart failure, end-stage renal disease, digestive disease, nonalcoholic fatty liver disease, urological disease, cancers, tumors, pain, asthma or chronic obstructive pulmonary disease by delivering an effective amount of a formulation to a tissue. In embodiments of the present invention, the formulation may include at least one of a gas, a vapor, a liquid, a solution, an emulsion, or a suspensions of one or more ingredients. In embodiments of the present invention, amounts of the formulation and or energy are effective to injure or damage tissue, nerves, and nerve endings in order to relieve disease symptoms.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/152,548, filed Apr. 24, 2015, and to PCT Application No.PCT/US2015/058296, filed Oct. 30, 2015, the disclosures of each of whichare hereby incorporated by reference.

BACKGROUND

Hypertension, or high blood pressure, is a major global health concern.An estimated 30 to 40% of the adult population in the world suffers fromthis condition. Furthermore, its prevalence is expected to increase,especially in developing countries. Diagnosis and treatment ofhypertension remain suboptimal, and most patients struggle to properlycontrol blood pressure.

Benign prostatic hyperplasia is a non-cancerous enlargement of theprostate gland, which affects more than 50% percent of men over the ageof 60. Early in life, the prostate is approximately the size of awalnut, weighing about 20 grams. Prostate enlargement, over time, isthought to be normal. With age, the prostate gradually increases to atleast twice its original size. Prostate growth causes pressure to buildagainst the neighboring urethra, leading to narrowing of this latterorgan, and ultimately resulting in urinary obstruction which makesurinating difficult.

Chronic obstructive pulmonary disease (COPD) is associated with twomajor airflow obstruction disorders: chronic bronchitis and emphysema.Chronic bronchitis results from inflammation of the bronchial airways.The bronchial airways connect the trachea to the lungs. Emphysema is adisease, which results from over-inflation of alveoli, or the air sacsin the lungs. This condition causes shortness of breath. Approximately16 million Americans suffer from COPD, the majority of which (80-90%)are lifetime smokers. COPD is a leading cause of death in the UnitedStates.

Asthma is a chronic respiratory disease characterized by excessivenarrowing of the airways and caused by inflammation of the airways,excess mucus production and airway hyper responsiveness, This narrowingof the airways makes breathing difficult and can significantly impactpatients' lives, limiting participation in numerous activities. Insevere cases, asthma attacks can be life-threatening. To date, there isno known cure for asthma.

Chronic sinusitis (CS) results from inflammation of the membrane liningin one or more paranasal sinuses and is typically associated withsignificant tissue damage. Approximately 37 million cases of CS arereported annually to the Centers for Disease Control and Prevention(CDC).

Diabetes is a metabolic condition, or combination of conditions, wherean individual experiences high concentrations of blood glucose. Thecondition is caused either by insufficient production of insulin withinthe body or by failure of cells to respond properly to insulin. Glycatedhemoglobin (HbA1c) is a marker of plasma glucose concentration and isclinically used for the diagnosis of diabetes. In humans, normal HbA1clevels are typically <6.0%, prediabetes HbA1c levels range from 6.0 to6.4%, and diabetes HbA1c levels exceed 6.5%.

Diabetes is one of the leading causes of death and disability in theUnited States and in other developed countries. It is associated withlong-term complications that affect almost every part of the body. Ithas been linked, for instance, to blindness, heart and blood vesseldisease, stroke, kidney failure, amputations, and nerve damage.

Within the United States, diabetes affects approximately 8 percent ofthe population and has resulted in costs that approach $250 billion.

Diabetes is typically classified as either type 1 (also referred to asinsulin-dependent diabetes or juvenile diabetes), wherein the patientfails to produce sufficient insulin, type 2 (also referred to asnon-insulin-dependent diabetes, adult-onset diabetes, or obesity-relateddiabetes), wherein the patient fails to respond properly to insulin, orgestational diabetes, a condition which develops late in pregnant women.

Type 2 diabetes is the most common form of diabetes, accounting for 90to 95% of overall cases. It is generally associated with older age,obesity, family history, previous history with gestational diabetes, andphysical inactivity. It is also more prevalent in certain ethnicities.Type 2 diabetes is also referred to as insulin-resistant diabetes, asthe pancreas typically produces sufficient amounts of insulin, but thebody fails to respond properly it. Symptoms associated with type 2diabetes include fatigue, frequent urination, increased thirst andhunger, weight loss, blurred vision, and slow healing of wounds orsores.

Obesity is another significant health concern, particularly in thedeveloped world. It is a complex, multifactorial and chronic conditioncharacterized by excess body fat, which results from an imbalancebetween energy expenditure and caloric intake. Although the causes ofthis imbalance are not completely understood, genetic and/or acquiredphysiologic events and environmental factors are thought to contribute.The adverse health effects associated with obesity, and morespecifically morbid obesity, have become well-established in recentyears. Such adverse effects include, but are not limited to,cardiovascular disease, diabetes, high blood pressure, arthritis, andsleep apnea. Generally, as a patient's body mass index (BMI) rises, thelikelihood of suffering the adverse effects linked to obesity alsorises.

Nonalcoholic fatty liver is another health concern, which occurs whenthe liver has trouble breaking down fats, causing fat to build up in theliver tissue of people who drink little or no alcohol. Nonalcoholicfatty liver disease is common and, for most people, causes no signs andsymptoms and no complications. But in some people with nonalcoholicfatty liver disease, the fat that accumulates can cause inflammation andscarring in the liver. This more serious form of nonalcoholic fattyliver disease is sometimes called nonalcoholic steatohepatitis. At itsmost severe, nonalcoholic fatty liver disease can progress to liverfailure.

SUMMARY OF THE INVENTION

The present invention provides new devices and methods for the treatmentof hypertension, diabetes, obesity, heart failure, end-stage renaldisease, digestive disease, nonalcoholic fatty liver disease, urologicaldisease, cancers, tumors, pain, asthma and chronic obstructive pulmonarydisease (COPD). The new methods involve chemical infusion formulationsand delivery systems and strategies. The methods focus on formulationdelivery to diseased tissues in the human body and may improve treatmentsafety and efficacy.

Embodiments of the present invention are directed to the treatment ofhypertension, diabetes, obesity, heart failure, end-stage renal disease,digestive disease, nonalcoholic fatty liver disease, cancers, tumors,pain, asthma and chronic obstructive pulmonary disease (COPD) bydelivery of an effective amount of a formulation to diseased tissues.Such formulations include gases, vapors, liquids, solutions, emulsions,and suspensions of one or more ingredients. Methods involve controlleddelivery of the formulations to lumen surfaces and tissues within thehuman body, resulting in modifications to those areas. Such methods canlead to denervation of nerves and nerve endings in the body lumens. Themethods can also include the beneficial severing of nerves and nerveendings in order to interrupt nerve communication. Temperature mayenhance the safety and efficacy of the treatment formulations. Thetemperature may range from −40 to 140° C., from −30 to 100° C., or from−30 to 80° C. In some embodiments, the formulation comprises one ofbinary, ternary or quaternary components, and may comprise more thanfour components. Methods of delivery include a less invasive,percutaneous approach and a non-invasive approach. Embodiments of thepresent invention provide a formulation and a delivery catheter, whichenhances absorption and penetration into body tissues and lumen nervesand nerve endings.

In one embodiment, at least one ingredient of the formulation is chosenfrom water, saline, hypertonic saline, phenols, methanol, ethanol,absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethyleneglycol, glycerol, acetic acid, lactic acid, propyl iodide, isopropyliodide, ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate,isopropyl acetate, ethyl lactate, urea, lipiodol, surfactants, andderivatives and combinations thereof.

In one embodiment, at least one ingredient of the formulation is a gas.The gas includes one of oxygen, nitrogen, helium, argon, air, carbondioxide, nitric oxide, vapors of organic and inorganic compounds, water,phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol,butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lacticacid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate,ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, andderivatives and combinations thereof.

In one embodiment, at least one ingredient of the formulation is asurfactant. The surfactant includes PEG laurate, Tween 20, Tween 40,Tween 60, Tween 80, PEG oleate, PEG stearate, PEG glyceryl laurate, PEGglyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate,polyglyceryl-6 palmitate, polyglyceryl-10 laurate, plyglyceryl-10oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEGsorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate,PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, organic acid,salts of any organic acid and organic amine, polyglycidol, glycerol,multiglycerols, galac(itol, ditethylene glycol), tritethylene glycol),tetra(e(hylene glycol), penta(ethylene glycol), poly(ethylene glycol)oligomers, ditpropylene glycol), tri(propylene glycol), tetra(propyleneglycol), penta(propylene glycol), poly(propylene glycol) oligomers, ablock copolymer of polyethylene glycol and polypropylene glyco ,Pluronic, Pluronic 85, and derivatives and combinations thereof.

In one embodiment, the formulation includes at least an oil, a fattyacid, and/or a lipid. In some embodiments, the at least oil, fatty acid,and/or lipid in the formulation is chosen from butanoic acid, hexanoicacid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid,hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoicacid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid,docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylicacid, capric acid, lauric acid, myristic acid, palmitic acid,palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleicacid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, crucicacid, lignoceric acid, natural or synthetic phospholipids, mono-, di-,or triacylglycerols, cardiolipin, phosphatidylglycerol, oho acid,phosphatidylcholine, alpha tocoferol, phosphatidylethanolamine,sphingomyelin, phosphatidylserine, phosphatidylinositol,dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine,dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine,phosphatidylethanolamines, phosphatidylglycerols, sphingolipids,prostaglandins, gangliosides, neobee, niosomes, and derivatives thereof.

In another embodiment, the formulation includes a therapeutic agent ordrug for nerve denervation. The therapeutic agent includes one of sodiumchannel blockers, tetrodotoxins, saxitoxins, decarbamoyl saxitoxins,neosaxitoxins, lidocaines, conotoxins, cardiac glycosides, digoxins,glutamates, staurosporines, amlodipines, verapamils, cymarins,digitoxins, proscillaridins, quabains, veratridines, domoic acids,ethanols, oleandrins, carbamazepines, aflatoxins, guanethidines, andguanethidine sulfates, In another enibodiment, the formulation includesa contrast agent for imaging nerve denervation. Such contrast agentsinclude one of iodine, ethyl iodide, sodium iodide, lipiodol, nonoxynoliodine, iobitridol, iohexol, iomeprol, iopamidol, iopentol, iopromide,ioversol, ioxilan, iotrolan, iodixanol, ioxaglate, and theirderivatives.

In one embodiment, the formulation includes an azeotrope. An azeotropeis a mixture of two or more ingredients that cannot be altered by simpledistillation. This happens because the vapor produced upon boiling hasconstituents proportional to those of the original mixture. Potentialformulation azeotropes include ethanol/water, ethanol/water/contrastagent, ethanol/water/surfactant, ethanol/water/contrastagent/surfactant, propanol/water, isopropanol/water, butanol/water,acetic acid/water, and their combinations.

In one embodiment, the formulation is in a gaseous or vapor state andincludes one or more ingredients. The vapor or gas formulation caninclude one of oxygen, nitrogen, helium, argon, air, carbon dioxide,nitric oxide, water, phenol, methanol, ethanol, absolute alcohol,isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol,acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide,methyl acetate, ethyl acetate, ethyl nitrate, isopropyl acetate, ethyllactate, and mixtures thereof. In one embodiment, the vapor formulationincludes one of binary, ternary or quaternary components, and maycomprise more than four components. The vapor formulation can include anazeotrope or a contrast agent, such as lipiodol or iodine, and mayinclude a surfactant and/or a therapeutic agent. The elevatedtemperature of the vapor formulation may range from 0° C. to 140° C.,from 15° C. to 100° C., or from 20° C. to 85° C.

In one embodiment, the formulation is in a liquid state and includes oneor more ingredients. The liquid formulation may include one of water,saline, hypertonic saline, phenol, methanol, ethanol, absolute alcohol,isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol,acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide,lipiodol, methyl acetate, ethyl acetate, ethyl nitrate, isopropylacetate, ethyl lactate, urea, surfactant, and others. The liquidformulation may include an azeotrope, contrast agent and/ora therapeuticagent. In one embodiment, the formulation may include one of binary,ternary, or quaternary components, and may also include more than fourcomponents. In some embodiments, the liquid formulation temperature mayrange from −40° C. to 140° C., from −30° C. to 100° C., or from −20° C.to 80° C. The liquid formulation may include a solution, a suspension,and an emulsion.

In one embodiment, the method for treatment of diseases includesinserting a delivery catheter percutaneously and/or transorally into thediseased tissues in the human body; using the catheter to infuse atherapeutic formulation into the tissues of the body, wherein the amountof the formulation delivered is effective to injure or damage thetissues, such as, for instance, by lowering blood pressure, reducingglucose level and relieving shortness of breath; optionally removing theformulation; and, lastly, withdrawing the delivery catheters from thebody. The diseases for this treatment include one of hypertension,pulmonary hypertension, diabetes, obesity, nonalcoholic fatty liverdisease, heart failure, end-stage renal disease, digestive disease,cancers, tumors, pain, asthma and chronic obstructive pulmonary disease(COPD). The body lumen applicable to such a treatment include renalarteries and veins, pulmonary arteries, vascular lumens, celiacarteries, common and proper hepatic arteries, gastroduodenal arteries,right and left hepatic arteries, splenic arteries, right and leftgastric arteries, nonvascular lumens, airways, the sinus, the esophagus,respiratory lumens, digestive lumens, the stomach, the duodenum, thejejunum, cancers, tumors, pain, and urological lumens. The digestivelumens applicable to such a treatment include the esophagus, thestomach, the duodenum, the jejunum, the small and large intestines, andthe colon. The formulations applicable to such a treatment includegases, vapors, liquids, solutions, emulsions, and suspensions of one ormore ingredients. If the formulation comprises vapors of one or moreingredients, the heat can be generated by condensation of the vaporsinto liquids in the tissue. If the formulation comprises liquids orsolutions, the cooling or heat can be generated from formulationtemperatures that fall below or exceed body temperature. The liquidformulation temperature may range from −40° C. to 140° C., from −30° C.to 100° C., or from −20° C. to 80° C. In one embodiment, the formulationtemperature may equal that of room temperature. In one embodiment, theformulation temperature may range from −40° C. to −20° C. In anotherembodiment, the formulation temperature may range from 15° C. to 80° C.In one embodiment, the formulation temperature may equal that of bodytemperature. In another embodiment, the formulation temperature mayrange from 50° C. to 80° C. In another embodiment, the temperature ofthe treated tissue may be lower than the formulation temperature andhigher than body temperature. The temperature of the treated tissue mayrange from −40° C. to 100° C., from −30° C. to 80° C., or from −20° C.to 80° C. In one embodiment, the temperature of the treated tissue mayrange from −40° C. to −20° C. In another embodiment, the temperature ofthe treated tissue may range from 15° C. to 80° C. In one embodiment,the temperature of the treated tissue may equal that of bodytemperature. In another embodiment, the temperature of the treatedtissue may range from 50 to 80° C. The delivery catheter applicable tosuch a treatment includes a needle or needle-based catheter under imagedguide. The imaged guide includes one of ultrasound, X-ray, CT scan, MRI,OCT or scopes. The delivery catheter can also be balloon-based. Suchballoon-based catheters can have single, double or triple balloons. Thedelivery catheters can also be infusion-based. The combination of aballoon and infusion catheter can also be used in the procedure. In oneembodiment, the method includes flushing from a catheter distal tip likewire lumen to protect and to dilute the migrated chemical, and toprevent the runaway chemical from entering the distal portion of theuntreated area; flushing from infusion catheter; flushing fromendoscope; removing or withdrawing the formulations from body tissuesand lumens following treatment, and flushing the target areapost-treatment with saline.

It is understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of the present invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an exemplary embodiment of a perspective view of a doubleballoon delivery catheter according to the present invention.

FIG. 2 is an embodiment of a side view of a distal portion of anexpanded dumbbell balloon.

FIG. 3A is an embodiment of a side view of an infusion balloon withholes on the balloon wall for chemical agent delivery.

FIG. 3B is an embodiment of a side view of a chemical agent deliverysystem positioned in a body lumen with an expanded balloon, the chemicalagent being confined mostly in between two large diameter segments.

FIG. 4A is an embodiment of a side view of an infusion device with achemical agent delivery tube attached to a balloon.

FIG. 4B is an embodiment of a side view of a dumbbell balloon infusiondevice with a tapered transition from larger to smaller diameter, and achemical agent delivery tube attached.

FIG. 5A is an embodiment demonstrating formulation infusion to an airwayusing a single balloon delivery catheter.

FIG. 5B is an embodiment demonstrating formulation infusion to an airwayusing a double balloon delivery catheter.

FIG. 5C is an embodiment demonstrating formulation infusion to a renalartery using a double balloon delivery catheter.

FIG. 6 is an embodiment of a partial cross-sectional view of a doubleballoon delivery catheter in a body lumen.

FIG. 7 is an embodiment of a partial cross-sectional view of atri-balloon on a multi-lumen shaft with an inflation lumen and an agentdelivery lumen.

FIG. 8A is an embodiment of a partial cross-sectional view of atri-balloon-combined infusion device with a reduced unoccupied spacebetween two larger diameter balloons in an expanded state.

FIG. 8B is an embodiment of a partial cross-sectional view of atri-balloon infusion device with differing balloon waist orientationsfor balloon attachment on a shaft.

FIG. 9A is an embodiment of a partial cross-sectional view of anexpanded double-balloon infusion device with infusion port(s) betweenthe balloons.

FIG. 9B is an embodiment of a partial cross-sectional view of anexpanded double-balloon infusion device with a tapered diameter changeand a smaller diameter in the middle section of the double-balloon.

FIG. 9C is an embodiment of a partial cross-sectional view of anexpandable double-balloon infusion device with combined two-stageballoons and a smaller diameter in the middle section of thedouble-balloon assembly.

FIG. 10A is an embodiment of a formulation infusion to the left gastricarteries with a single balloon delivery catheter.

FIG. 10B is an embodiment of a formulation fusion to the hepaticarteries with a single balloon delivery catheter.

FIG. 11 is an embodiment of a formulation infusion to the duodenum witha triple-balloon delivery catheter.

FIG. 12 is a bar graph demonstrating norepinephrine (NE) reductionfollowing renal denervation in ethanol- vs. control-treated groups.

FIG. 13 is a curve demonstrating weight change following duodenaltreatment with an acetic acid agent.

FIG. 14 is a curve demonstrating weight change following duodenaltreatment with an ethanol agent.

FIG. 15 is an embodiment of a metal infusion tube with Bard trianglefeatures (as shown by white arrows).

FIG. 16 is a histopathologic image demonstrating severed renal nerves(as shown by black arrows) following ethanol treatment.

DETAILED DESCRIPTION

Reference will now be made in detail to certain embodiments of thedisclosed subject matter, examples of which are illustrated in part inthe accompanying drawings. While the disclosed subject matter will bedescribed in conjunction with the enumerated claims, it will beunderstood that the exemplified subject matter is not intended to limitthe claims to the disclosed subject matter.

Throughout this document, values expressed in a range format should beinterpreted in a flexible manner to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges encompassedwithin that range as if each numerical value and sub-range is explicitlyrecited. For example, a range of “about 0.1% to about 5%” or “about 0.1%to 5%” should be interpreted to include not just about 0.1% to about 5%,but also the individual values (e.g., 1%, 2%, 3%, and 4%) and thesub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within theindicated range. The statement “about X to Y” has the same meaning as“about X to about Y,” unless indicated otherwise. Likewise, thestatement “about X, Y, or about Z” has the same meaning as “about X,about Y, or about Z,” unless indicated otherwise.

In this document, the terms “a,” “an,” or “the” are used to include oneor more than one unless the context clearly dictates otherwise. The term“or” is used to refer to a nonexclusive “or” unless otherwise indicated.The statement “at least one of A and B” has the same meaning as “A, B,or A and B.” In addition, it is to be understood that the phraseology orterminology employed herein, and not otherwise defined, is for thepurpose of description only and not of limitation. Any use of sectionheadings is intended to aid reading of the document and is not to beinterpreted as limiting; information that is relevant to a sectionheading may occur within or outside of that particular section.

In the methods described herein, the acts can be carried out in anyorder without departing from the principles of the invention, exceptwhen a temporal or operational sequence is explicitly recited.Furthermore, specified acts can be carried out concurrently unlessexplicit claim language recites that they be carried out separately. Forexample, a claimed act of doing X and a claimed act of doing Y can beconducted simultaneously within a single operation, and the resultingprocess will fall within the literal scope of the claimed process.

The term “about” as used herein can allow for a degree of variability ina value or range, for example, within 10%, within 5%, or within 1% of astated value or of a stated limit of a range, and includes the exactstated value or range.

The term “substantially” as used herein refers to a majority of, ormostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%,98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or100%.

Embodiments of the present invention are directed to the treatment ofdisease by delivery of an effective amount of formulation to targettissues in a body lumen. The disease may be one of hypertension,pulmonary hypertension, diabetes, obesity, nonalcoholic fatty liverdisease, heart failure, end-stage renal disease, digestive disease,cancers, tumors, pain, asthma or chronic obstructive pulmonary disease(COPD). The cancers include adrenal, bladder, cervical, colon,esophageal, gallbladder, kidney, liver, lung, ovarian, pancreatic,prostatic, rectal, stomach, and uterine. The formulations include gases,vapors, liquids, solutions, emulsions, and suspensions of one or moreingredients. The methods involve delivery of the formulations to lumensurfaces, tissues and nerves in the human body in order to modify suchsurfaces, tissues and nerves. The body lumen include a renal artery anda vein, a pulmonary artery, a vascular lumen, a celiac artery, a commonhepatic artery, a proper hepatic artery, a gastroduodenal artery, arighthepatic artery, a left hepatic artery, a splenic artery, aright gastricartery, a left gastric artery, a blood vessel, a nonvascular lumen, anairway, a sinus, an esophagus, a respiratory lumen, a digestive lumen, astomach, a duodenum, a jejunum, a cancer tissue, a tumor, and aurological lumen. The digestive lumens include the esophagus, thestomach, the duodenum, the jejunum, the small and large intestines, andthe colon. The temperature may enhance the safety and efficacy oftreatment formulations. The temperature may range from −40° C. to 140°C., from 30° C. to 100° C., or from −20° C. to 80° C. The temperature ofthe treated tissue may be different from the formulation temperature.The temperature of the treated tissue may range from −40° C. to 100° C.,or from −30° C. to 80° C. The amount of formulation and energy deliveredmay be effective to injure, damage or eliminate diseased tissues, suchas, for instance, by lowering blood pressure, shrinking tumors,relieving pain, or relieving symptoms of asthma and COPD. The energy orheat can enhance the injury/damage/elimination effect by acceleratingthe reaction rate between the formulation and tissues. Methods ofdelivery include delivery of the formulations to ablate nerves thatsurround the human body lumens. Such methods include removing orwithdrawing the formulations from the tissue or lumen after treatment.

In one embodiment, the formulation is a single chemical or one ofbinary, ternary, or quaternary components, and may also include morethan four components. In one embodiment, the delivery system may includeless invasive percutaneous approaches or non-invasive approaches.Embodiments of the present invention include a formulation comprisingone or more ingredients that enhance both surface modification of thebody lumen and absorption and penetration into tissues and nerves andnerve endings of the body lumens.

In one embodiment, the ingredient of the formulation is chosen fromwater, saline, hypertonic saline, phenol, methanol, ethanol, absolutealcohol, isopropanol, propanol, butanol, isobutanol, ethylene glycol,glycerol, acetic acid, lactic acid, propyl iodide, isopropyl iodide,ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropylacetate, ethyl lactate, urea, lipiodol, surfactant, and derivatives andcombinations thereof.

In one embodiment, the ingredient of the formulation includes a gas. Thegas can be chosen from oxygen, nitrogen, helium, argon, air, carbondioxide, nitric oxide, vapors of organic and inorganic compounds, water,phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol,butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lacticacid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate,ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, andmixtures thereof.

In one embodiment, the ingredient in the formulation includes asurfactant. In some embodiments, the surfactant is chosen from PEGlaurate, Tween 20, Tween 40, Tween 60, Tween 80, PEG oleate, PEGstearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glycerylstearate, polyglyceryl laurate, plyglyceryl oleate, polyglycerylmyristate, polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate,polyglyceryl-10, laurate, plyglyceryl-10 oleate, polyglyceryl-10myristate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEGsorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate,PEG oleyl ether, PEG laurayl ether, organic acid, salts of any organicacid and organic amine, polyglycidol, glycerol, multiglycerols,galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethyleneglycol), penta(ethylene glycol), poly(ethylene glycol) oligomers,di(propylene glycol), tri(propylene glycol), tetra(propylene glycol),penta(propylene glycol), poly(propylene glycol) oligomers, a blockcopolymer of polyethylene glycol and polypropylene glycol, Pluronic,Pluronic 85, and derivatives and combinations thereof. In someembodiments, the content of the surfactant in the formulation may rangefrom 0.1% by weight to 80% by weight, from 0.5% by weight to 50% byweight, or from 1% by weight to 15% by weight.

In one embodiment, the formulation includes at least one of an oil, afatty acid, and/or a lipid. The at least one of an oil, a fatty acid,and a lipid in the formulation is chosen from butanoic acid, hexanoicacid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid,hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoicacid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid,docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylicacid, capric acid, lauric acid, myristic acid, palmitic acid,palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleicacid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucicacid, lignoceric acid, natural or synthetic phospholipids, mono-, di-,or triacylglycerols, cardiolipin, phosphatidylglycerol, phosphatidicacid, phosphatidylcholine, alpha tocoferol, phosphatidylethanolamine,sphingomyelin, phosphatidylserine, phosphatidylinositol,dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine,dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine,phosphatidylethanolamines, phosphatidylglycerols, sphingolipids,prostaglandins, gangliosides, neobee, niosomes, and derivatives thereof.

In another embodiment, the formulation includes a therapeutic agent ordrug for nerve denervation and surface modification. The therapeuticagent is one of sodium channel blockers, tetrodotoxins, saxitoxins,decarbamoyl saxitoxins, vanilloids, neosaxitoxins, lidocaines,conotoxins, cardiac glycosides, digoxins, glutamates, staurosporines,amlodipines, verapamils, cymarins, digitoxins, proscillaridins,quabains, veratridines, domoic acids, ethanols, oleandrins,carbamazepines, aflatoxins, guanethidines, or guanethidine sulfates. Inanother embodiment, the formulation includes a contrast agent forimaging nerve denervation. Such contrast agents include iodine, ethyliodide, sodium iodide, lipiodol, nonoxynol iobitridol, iohexol,iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan,iodixanol, ioxaglate, and their derivatives. The content of the contrastagent in the formulation may range from 2 to 25% by weight, or from 5 to15% by weight.

In one embodiment, the formulation includes an azeotrope. An azeotropeis a mixture of two or more ingredients that cannot be altered by simpledistillation. This happens because the vapor produced upon boiling hasconstituents proportional to those of the original mixture. Theazeotrope is chosen from ethanol/water, ethanol/water/contrast agent,ethanol/water/surfactant, ethanol/water/contrast agent/surfactant,propanol/water, iso-propanol/water, butanol/water, and aceticacid/water.

In one embodiment, the formulation is in a gaseous or vapor state,including one or more ingredients. In one embodiment, the gas or vaporformulation includes one of oxygen, nitrogen, helium, argon, air, carbondioxide, nitric oxide, and vapors of organic and inorganic compounds.The vapors of the organic and inorganic compounds include one of water,phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol,butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lacticacid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate,ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate, andtheir mixtures.

In one embodiment, the vapor formulation includes at least one contrastagent, such as lipiodol or iodine, or an azeotrope, and may also includea surfactant and/or a therapeutic agent. In one embodiment, the vapor isone of binary, ternary, or quaternary components, and may also includemore than four components. The vapor formulation temperature may rangefrom 0° C. to 140° C., from 15° C. to 100° C., or from 30° C. to 80° C.

In one embodiment, the formulation is in a liquid state, including oneor more ingredients. The liquid formulation includes one of water,saline, hypertonic saline, phenol, methanol, ethanol, absolute alcohol,isopropanol, propanol, butanol, isobutanol, ethylene glycol, glycerol,acetic acid, lactic acid, propyl iodide, isopropyl iodide, ethyl iodide,lipiodol, methyl acetate, ethyl acetate, ethyl nitrate, isopropylacetate, ethyl lactate, urea, surfactant, and others. In one embodiment,the liquid formulation includes a contrast agent and/or an azeotrope,and may also include a therapeutic agent. In one embodiment, the liquidformulation is one of binary, ternary, or quaternary components, and mayalso include more than four components. In one embodiment, the liquidformulation includes a solution, an emulsion, or a suspension. Theliquid formulation temperature may range from −40° C. to 140° C., from−30° C. to 100° C. or from −30° C. to 80° C. In one embodiment, theformulation temperature may be room temperature. In one embodiment, theformulation temperature may range from −40° C. to −20° C. In anotherembodiment, the formulation temperature may range from 15 C. to 80° C.In one embodiment, the formulation temperature may be equal to bodytemperature. In another embodiment, the formulation temperature mayrange from 50° C. to 80° C.

In one embodiment, the method for treatment of disease includesinserting a delivery catheter percutaneously or transorally into thebody; using the catheter to infuse a formulation to diseased tissues orlumens in the body; optionally removing or withdrawing the formulationfrom the diseased tissue or body lumen; optionally diluting theformulation from the diseased tissue or body lumen with saline solution;and, withdrawing the delivery catheters from the body. The diseases fortreatment include hypertension, pulmonary hypertension, diabetes,obesity, nonalcoholic fatty liver disease, heart failure, end-stagerenal disease, digestive disease, urological disease, cancers, tumors,pain, asthma and chronic obstructive pulmonary disease (COPD). Thecancers include adrenal, bladder, cervical, colon, esophageal,gallbladder, kidney, liver, lung, ovarian, pancreatic, prostatic,rectal, stomach, and uterine. The body lumen include renal arteries,vascular lumens, celiac arteries, common and proper hepatic arteries,gastroduodenal arteries, right and left hepatic arteries, splenicarteries, right and left gastric arteries, nonvascular lumens, airways,sinuses, the esophagus, respiratory lumens, digestive lumens, thestomach, the duodenum, the jejunum, and urological lumens. The digestivelumens include the esophagus, the stomach, the duodenum, the jejunum,the small and large intestines, and the colon. The formulations includegases, vapors, liquids, solutions, emulsions, and suspensions of one ormore ingredients. In embodiments where the formulation includes vaporsof one or more ingredients, the heat can be generated by condensation ofthe vapors into liquids in the tissue. In embodiments where theformulation includes liquids or solutions, cooling or heat can begenerated from formulation temperatures that fall below or exceed bodytemperatures. The liquid formulation temperature may range from −40° C.to 140° C., from −30° C. to 100° C. or from −30° C. to 80° C. In oneembodiment, the temperature of the treated tissue may be different fromthe formulation temperature and lower or higher than body temperature.The temperature of the treated tissue may range from 15° C. to 100° C.,from 20° C. to 90° C. or from 36° C. to 80° C. In another embodiment,the temperature of the treated tissue may range from −40° C. to −20° C.In some embodiments, the delivery catheter is a needle or a needle-basedcatheter under imaged guide. The imaged guide is one of ultrasound,X-ray, CT-scan, MRI, OCT or scopes. The delivery catheter can also beballoon- or infusion-based. Balloon-based catheters can have single,double or triple balloons. Infusion catheters can have a dumbbellballoon. Typically, there are three sections of the dumbbell infusionballoon: proximal, distal and middle. The middle section has a smallerdiameter with or without infusion holes, and the proximal and the distalsections of the balloon have a larger diameter without infusion holes.The infusion is from an expandable catheter component if the middlesection of a dumbbell balloon has holes (FIGS. 3A and 3B) and is definedas an expandable infusion method. The initial infusion pressure mayrange from 0.1 atm to 14 atm, from 1 atm to 10 atm, or from 3 atm to 8atm, depending upon applications. The infusion time may range from OAminutes to 2 hours, from 0.5 minute to 30 minutes, or from 1 minute to10 minutes. During the infusion time period following initial infusionpressure, the balloon pressure may be in a range from 0.1 atm to 3 atm,from 0.1 atm to 2 atm, and from 0.3 atm to 1 atm. The formulationinfusion temperature may range from −40° C. to 150° C., from −30° C. to100° C. or from −20° C. to 80° C.

In one embodiment, the infusion feature can be made from ahypotube/tube, either made of plastics or metals, which is attached to ano-hole dumbbell-type balloon catheter. The infusion is from anon-expandable catheter component when treatment formulation isdelivered through holes on the hypotube/tube and the hypotube/tube ismoving with the balloon towards the vessel wall; this infusion isdefined as a hybrid method including the combination of non-expandableand expandable infusion methods. Typically, the hole section of thehypotube/tube is aligned along the middle section of the dumbbellballoon to control the location of formulation flow.

In another embodiment, the infusion lumen can be placed inside thecatheter shaft, such as in the multi-lumen shaft for the non-expandableinfusion method. In this case, holes are located on the non-expandablesection between the balloons on the shaft (FIGS. 7, 8A-8B, 9A-9C). Moredetailed examples of the device, such as double-balloon andtriple-balloon infusion catheters, are shown in the following sections.

In one embodiment, the metal hypotube can have a Bard triangle feature,which will enhance the diffusion of a formulation by creating very smallholes inside the vessel wall or in the tissues. The height of the Bardtriangle can range from 0.25 to 2 mm. This infusion method is a hybridmethod.

In one embodiment, the formulation comprises ethanol. This formulationcan be delivered to the tissues of the body lumen as vapor or liquid.The vapor or liquid formulation temperature may range from −40° C. to150° C., from −30° C. to 100° C., or from −20° C. to 80° C. Thetemperature of the tissue may range from −40° C. to 90° C., or from −30°C. to 80° C. In one embodiment, the formulation consists essentially ofethanol. In one embodiment, the formulation consists of ethanol.

In one embodiment, the formulation is a mixture of ethanol and water.The ethanol content can range from 10 to 100% by weight. Thisformulation can be delivered to the tissues of the body lumen as vaporor liquid. The vapor or liquid formulation temperature may range from−40° C. to 150° C., from −30° C. to 100° C., or from −20° C. to 80° C.The temperature of the tissue may range from −40° C. to 90° C., from−30° C. to 80° C. The ethanol/water formulation may be a positiveazeotrope. The azeotrope may be 95.63% ethanol and 4.37% water byweight. Ethanol boils at 78.4° C., water boils at 100° C., and theazeotrope boils at 78.2° C., which is lower than either of itsconstituents. 78.2° C. is the minimum temperature at which anyethanol/water solution can boil at atmospheric pressure.

In another embodiment, the formulation is a mixture of vapors comprisingwater, ethanol and oxygen. In another embodiment, the formulation is amixture of vapors comprising water, ethanol and air. In anotherembodiment, the formulation is a mixture of vapors comprising water,ethanol, oxygen and nitrogen. The formulations with oxygen and air areespecially useful for treating asthma and COPD.

In another embodiment, the formulation is a mixture of vapors comprisingwater, ethanol and iodine, wherein an effective amount of the iodinevapor is included so as to be able to image the mixture of vapors in thewall of the body lumen. In another embodiment, the formulation is amixture of liquids comprising water, ethanol and a surfactant. Inanother embodiment, the formulation is a mixture of liquids comprisingwater, ethanol and a contrast agent, wherein an effective amount of thecontrast agent is included so as to be able to track the mixture in thewall of the body lumen by X-ray. The contrast agent is one of iodine,ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine, iobitridol,iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan,iotrolan, iodixanol, ioxaglate, and derivatives thereof. The content ofthe contrast agent in the formulation may range from 2 to 20% by weight,or from 5 to 15% by weight.

In one embodiment, the formulation is a mixture of acetic acid andwater. The acetic acid content of the formulation may range from 1 to100% by weight, from 10 to 75% by weight, or from 20 to 50% by weight.The formulation may be delivered to tissues of the body lumen as vaporsor liquid. The vapor or liquid formulation temperature may range from−40° C. to 100° C., from −30° C. to 100° C., or from −30° C. to 80° C.The temperature of the tissue may range from −30° C. to 80° C., from 60°C. to 80° C. or from −30° C. to −20° C. The temperature of the tissuemay range from −40° C. to 0° C., or from −30° C. to −20° C. The aceticacid content in the formulation may range from 2% by weight to 75% byweight, or from 10% by weight to 60% by weight.

In another embodiment, the formulation is a mixture of liquidscomprising ethanol and lipiodol (LIPIODOL ULTRA-FLUIDE), wherein aneffective amount of lipiodol is included so as to be able to image themixture of vapors in the wall of the body lumen and to also injure thetarget nerve tissue. The lipiodol content of the formulation may rangefrom 10% by weight to 80% by weight, from 15% by weight to 75% byweight, or from 20% by weight to 50% by weight. In another embodiment,the formulation is a mixture of liquids comprising water and lipiodol.The lipiodol content of the formulation may range from 10% by weight to80% by weight, from 15% by weight to 75% by weight, or from 20% byweight to 50% by weight. In another embodiment, the formulation is amixture of liquids comprising acetic acid and lipiodol. The content oflipiodol in the formulation may range from 10% by weight to 80% byweight, from 15% by weight to 75% by weight, or from 20% by weight to50% by weight.

In one embodiment, a delivery catheter is used in the invention toinfuse the formulation to the tissues of the human body. The deliverycatheter is a needle or needle based catheter under X-ray orultrasound-imaged guide. The delivery catheter can be balloon-based withsingle, double or triple balloons. The delivery catheters can also beinfusion-based. The combination of balloon and infusion catheter canalso be used in the procedure. The balloon in the infusion system shouldbe able to confine the formulation within the balloon well andappropriately control the formulation volume.

In one embodiment, a dilating balloon catheter is used in the inventionfor delivery of active materials to a target location in the body lumenof a patient, the dilating balloon catheter comprising a proximal end, adistal end, a wire, a lumen, a balloon inflation lumen, a formulationinfusion lumen and/or a vacuum lumen, an expandable balloon section anda non-expandable shaft section, wherein the expandable balloon sectioncomprises at least one section and the non-expandable shaft sectioncomprises at least one section, at least one first section of theexpandable section and/or the non-expandable section having a pluralityof voids, wherein the voids are micro-holes, and at least one secondsection of the expandable section and/or the non-expandable shaftsection having no voids. The expandable section or non-expandablesection of the dilating balloon catheter has at least one void thatallows the formulation to penetrate into the wall of the body lumen at apressure higher than that of the body lumen. The expandable section ornon-expandable section has no void that allows the balloon to dilate thebody lumen at a pressure higher than that of the body lumen.

As shown in FIG. 1, a delivery catheter 10 has an elongated shaft 11with at least one inner lumen, a distal end 13, and a proximal end 14.At the distal end 13 are proximal 20 and distal 21 lumen-conformingballoons. In any configuration, the tubing of the catheter shaft 11 maybe extruded from plastic materials, e.g. thermoplastics, polyimides,polyetherimides, polyethylenes, polyurethanes, polyesters, polyamides,Pebax, nylons, fluorinated polyurethanes, polyether ether ketones,polysulfones, or the like. The catheter shaft 11 may be extruded orformed with a variety of lumen cross-sections, including circular orelliptic lumens. Further, as shown in FIG. 1, the catheter 10 may beequipped with a distal balloon inflation port 40 for inflation of thedistal balloon 21 and a proximal balloon inflation port 41 for inflationof the proximal balloon 20, rendering the proximal 20 and distal 21balloons separately inflatable. The lumen-conforming balloons areballoons that can be inflated at a pressure less than that needed todeform the lumen wall. The balloon material is selected to be flexibleand usable at high temperatures, such that the balloon, when inflated,is compliant. In one embodiment, the balloon material is one ofpolyamides, nylons, Pebax, polyesters, polyethylene teraphthalates ortheir copolymers. The diameter of the balloons can range from about 2millimeters to about 40 millimeters, depending on the diameter of thetreatment site. In one embodiment, the diameter of each balloon is about2 millimeters (“mm”). Alternatively, the diameter of each balloon isabout 3 millimeters, or, alternatively, about 4 millimeters, or,alternatively, about 5 millimeters, or, alternatively, about 6millimeters, or, alternatively, about 7 millimeters, or, alternatively,about 8 millimeters, or, alternatively, about 9 millimeters, or,alternatively, about 10 millimeters, or, alternatively, about 12millimeters, or, alternatively, about 15 millimeters, or, alternatively,about 20 millimeters, or, alternatively, about 25 millimeters, or,alternatively, about 30 millimeters, or, alternatively, about 35millimeters, or, alternatively, about 40 millimeters.

In one embodiment, at least one marker band 22 b is located proximallyto the proximal balloon 20 and at least one marker band 23 a is locateddistally to the distal balloon 21. The balloon catheter may be a rapidexchange or over-the-wire catheter made of any suitable biocompatiblematerial. Marker bands can also be positioned on the other ends ofballoons (22 a and 23 b), 25 is the segment in between balloons 21 and21 with at least one infusion hole, 30 is the non-expandable section; 31and 32 are micro-voids or holes; 24 is the shaft proximal to the balloonsection, 40 and 41 are the ports for balloon inflation for the distaland proximal balloons, respectively. 42 is the infusion port forchemical formulation.

The material of balloon 20 and 21 is made of one of polyesters,polyamides, nylon 12, nylon 11, polyamide 12, block copolymers ofpolyether and polyamide, Pebax, polyurethanes, or block copolymers ofpolyether and polyester. The diameter of balloon 21 is equal to or lessthan that of balloon 20.

In one embodiment, a schematic dumbbell balloon is shown in FIG. 2. Inan expanded state, its middle diameter D2 is smaller than both of itsend diameters D1 and D3, D1 and D3 can be equal in length or different.Each diameter section has its own length, L1, L2 and L3, respectively.For simple illustration, a dumbbell-type balloon is used for thedescriptions below. However, other similar-type balloons like amulti-groove balloon, in which the grooves are located in the middlesection of the balloon, can achieve the same feature/function. Thedesign of the dumbbell-type balloon shape allows for the balloon to havebetter infusion volume control and formulation location control insidethe targeted vessel because the two larger ends block the formulationflow path. In one embodiment, the delivered formulation will be confinedmostly to the middle section of the smaller diameter, as shown in FIG.2. A controlled treatment dosage is required for procedural safety,which means that the diameter ratio between the larger and smallerdiameters on the dumbbell balloon is determined by clinical dosingneeds. To define the diameter combination on the dumbbell balloon, thevolume per surface area is used, and is calculated from the volume gap(unoccupied space over small diameter section) between the two largerdiameter ends relative to the smaller diameter middle section. Theequation of the ratio calculation is:

Volume/Surface area=(D1² −D2²)÷(4*D1)   Equation 1

Where D1 is the diameter of the larger diameter balloon portion and D2is the diameter of the smaller diameter balloon portion.

The ratio of volume/surface area can range from 0.1 mm to 10 mm, from0.2 mm to 5 mm, or from 0.3 mm to 2 mm. The dose of chemical agent can,thereby, be constant and independent of balloon or vessel size. Thevalue of the ratio is determined by clinical treatment needs (dosingrequirements). The dumbbell balloon or multi-groove balloon can be madefrom a secondary heat-shrinking process involving a regular cylindricalballoon or by direct molding into form. The balloon body diameterdifference between the larger diameter ends and the middle smallerdiameter section is determined by a pre-defined value of volume/surfacearea ratio, which is calculated using Equation 1. For example, for thecombination of 6 mm and 8 mm balloons, the calculated volume/surfacearea ratio would be 0.88 mm.

Overall balloon body diameter and length can range from 2 to 40 mm and10 to 100 mm, respectively. Conventional balloon cone angle or shape isacceptable for the applications, however, round or radius cone shape ispreferred.

Any balloon materials that are compatible with the formulations can beused for balloon making, such as polyethylenes, polyolefin elastomers,natural rubbers, polyesters like PET and PBT and their block copolymersincluding thermoplastic elastomers like Hytrel, and polyamides likenylon 12 and nylon 11 and their block copolymers including thermoplasticelastomers like Pebax.

In one embodiment, a schematic view of a dumbbell balloon infusioncatheter is shown in FIG. 3A, with 4 holes arranged 90 degrees apart inthe middle smaller diameter balloon section, which is modified from FIG.2 with tapered transitions between different diameters. The liquidformulation may be delivered from the balloon inflation lumen throughthe holes on the balloon; this is an expandable infusion method. In thisexample, the formulation functions in two roles: inflating the balloonand serving as a treatment agent. FIG. 3B is a schematic view of aninfusion balloon catheter inflated and positioned inside a vessel. Themajority of the delivered treatment formulation is confined to the spacecreated by the smaller balloon body and two larger balloon shoulderswithin the vessel wall.

To enhance the diffusion distance of the chemical treatment agent, aratio of balloon outer diameter (OD) to vessel interior diameter (ID)that is larger than one, in which the vessel is over dilated at aspecific controlled level may be used. The ratio can range from 1.01 to10, 1.10 to 5, or from 1.20 to 1.35.

The micro holes on the balloon for delivering the chemical agent can becreated by a micro-punching or drilling process directly on the balloonbody wall. The suitable hole size can range from 5 microns to 500microns, or from 20 microns to 250 microns on the balloon wall. Thesevalues appropriately consider the balance between balloon inflation,infusion rate and formulation flow control. If the hole size is toolarge, the formulation volume may not be controllable due to over flow.Geometrically, the holes are typically arranged in the middle section ofthe small diameter area; however, they can be placed in a different wayor pattern on the balloon, for purposes of delivering formulation. Theholes on the balloon may also be arranged along the circumference of theballoon body wall at the center of the smaller diameter section. Thenumber of holes can range from 2 to 10 or more and the size of holes canrange from 25 microns to 100 microns.

The dumbbell balloon in FIG. 3A can be considered as one groove balloonwith four evenly distributed holes circumferentially, the balloonembodiment above also including multiple grooves on the balloon and eachgroove having its own group of holes for infusion. For example, athree-groove balloon could be made from an 80 mm long length balloon,and the infused agent could be confined within each groove. The clinicaloutcome of a multi-groove balloon would be the same as that of theregular dumbbell balloon shown in FIG. 3A, if their respectivevolume/surface area ratios were equal. FIG. 3A is a device for anexpandable infusion method.

In another embodiment, as shown in FIGS. 4A-4B, the chemical agent isdelivered through a thin tube attached to the catheter at a distal andproximal balloon. In this example, a dumbbell balloon catheter withoutholes on the balloon is used for the infusion system. FIGS. 4A-4B aredevices for a hybrid infusion method. The formulation delivery tube hasmultiple holes located within the balloon section of the smallerdiameter. The hole size on the tube can range from 25 microns to 1 mm.The number of holes varies depending on the length of the smallerdiameter balloon section. A distance between holes can range from 2 mmto 5 mm.

Due to the incorporation of the infusion tube in the embodiments shownin FIGS. 4A-4B, the balloon inflation and formulation infusion occurthrough separate, independent procedures. The balloon, for instance, isfirst inflated to a predetermined pressure; the effective volume of thechemical agent is next delivered through the tube to the treatment sitewhile the remainder of the formulation is confined to the middle sectionof the smaller balloon diameter area. The infusion tube used on thecatheter can be made from thermal plastics like polyethylene, nylons orPebax, or metals or metal alloys like stainless steel or nitinol, ornitinol hypotube for its super elastic property.

An advantage of using metal or metal alloy tubing over plastic tubing isthe presence of additional features for formulation delivery. Forexample, the Bard triangle feature can be added to a metal tube (FIG.15). The sharp tip of the Bard triangle would serve to pinch into thetissue wall when the balloon is inflated against the vessel wall.Compared to the round hole version, this delivery system would enabledeeper diffusion of the chemical agent into the vessel tissue in partdue to the piercing of the tissue. If a deeper diffusion over a widervessel wall area is needed, the balloon can be inflated and deflatedseveral times and rotated after each inflation/deflation cycle. Thiswould result in additional punctured holes on the vessel wall and wouldenable the formulation to diffuse through deeper and faster. The heightof the Bard triangle can range from 0.25 mm to 2 mm, or from 0.5 mm to 1mm.

In one embodiment, a schematic view of a balloon delivery catheterpositioned within the left main bronchus for treatment of asthma andCOPD is shown in FIGS. 5A and 5B. The delivery catheter 198 of FIGS. 5Aand 5B can treat airways that are distal to the main bronchi 21 and 22.For example, the delivery catheter 198 can be positioned in variousairways in segments of lungs to affect remote distal portions of thebronchial tree 27. The delivery system 198 can be navigated throughtortuous airways to perform a wide range of procedures, such as, forexample, denervation of a portion of a lobe, an entire lobe, multiplelobes, or one or both lungs. In some embodiments the lobar bronchi aretreated to denervate lung lobes. For example, one or more treatmentsites along a lobar bronchus may be targeted to denervate an entire lobeconnected to that lobar bronchus. Left lobar bronchi can be treated toaffect the left superior lobe and/or the left inferior lobe. Right lobarbronchi can be treated to affect the right superior lobe, the rightmiddle lobe, and/or the right inferior lobe. Lobes can be treatedconcurrently or sequentially. In some embodiments, a physician can treata lobe. Based on the effectiveness of the treatment, the physician canconcurrently or sequentially treat additional lobe(s). In this manner,different isolated regions of the bronchial tree can be treated.

The delivery catheter 198 can also be used in segmental or sub-segmentalbronchi. Each segmental bronchus may be treated by delivering theformulation to a single treatment site along the segmental bronchus. Forexample, the formulation can be delivered to each segmental bronchus ofthe right lung. In some procedures, one or two applications of theformulation can treat most of or the entire right lung. Depending on theanatomical structure of the bronchial tree, segmental bronchi can oftenbe denervated using one or two applications.

The delivery catheter 198 can affect nerve tissue while maintaining thefunction of other tissues or anatomical features, such as the mucousglands, cilia, smooth muscle, body lumens (e.g., blood vessels), and thelike. Nerve tissue includes nerve cells, nerve fibers, dendrites, andsupporting tissue, such as neuroglia. Nerve cells transmit electricalimpulses, and nerve fibers are prolonged axons that conduct theimpulses. The electrical impulses are converted to chemical signals tocommunicate with effector cells or other nerve cells. By way of example,the delivery catheter 198 is capable of denervating a portion of anairway of the bronchial tree 27 to attenuate one or more nervous systemsignals transmitted by nerve tissue. Denervating can include severingthe nerve tissue of a section of a nerve trunk to prevent signals fromtraveling through that specific area to more distal locations along thebronchial tree. If a plurality of nerve trunks extends along an airway,each nerve trunk can be severed. As such, the nerve supply along asection of the bronchial tree can be cut off. When the signals are cutoff, the distal airway smooth muscle relaxes, leading to airwaydilation. This airway dilation reduces airflow resistance so as toincrease gas exchange in the lungs, thereby alleviating, or eliminatingone or more clinical manifestations, such as breathlessness, wheezing,chest tightness, and the like. Tissue surrounding or adjacent to thetargeted nerve tissue may be affected but not permanently severed. Insome embodiments, for example, the bronchial blood vessels along thetreated airway can deliver a similar amount of blood to the bronchialwall tissues, and the pulmonary blood vessels along the treated airwaycan deliver a similar amount of blood to the alveolar sacs at the distalregions of the bronchial tree 27 before and after treatment. These bloodvessels can continue to transport blood to maintain sufficient gasexchange. In some embodiments, airway smooth muscle is not injured to asignificant extent. For example, a relatively small section of smoothmuscle in an airway wall which does not appreciably impact respiratoryfunction may be reversibly altered. If the formulation is employed at aregulated temperature to injure nerve tissue outside of the airways,that formulation will not reach a significant portion of thenon-targeted smooth muscle tissue.

The delivery system 198 of FIGS. 5A and 5B includes a treatmentcontroller 202 and an intraluminal elongate assembly 200 connected tothe controller 202. The elongate assembly 200 can be inserted into thetrachea 20 and navigated into and through the bronchial tree 27 with orwithout utilizing a delivery assembly. The elongate assembly 200includes a distal tip 203 capable of selectively affecting tissue.

The controller 202 of FIG. 5A can include one or more processors,microprocessors, digital signal processors (DSPs), field programmablegate arrays (FPGA), application-specific integrated circuits (ASICs),memory devices, buses, power sources, pumps, formulation resources,vapor resources, liquid resources, contrast resources, vapor generators,desired temperature formulation generators, and the like.

The distal tip 203 of FIGS. 5A-5B can target various sites in the lungs10, including, without limitation, nerve tissue, fibrous tissue,diseased or abnormal tissue, muscle tissue, blood, blood vessels, andvarious anatomical features (e.g., membranes, glands, cilia, and thelike).

In one embodiment, a schematic view of a double balloon deliverycatheter positioned within a renal artery is shown in FIG. 5C. Theballoon catheter 107 of FIG. 5C can treat hypertension. The formulationis infused to the wall of the renal arteries adjacent to the renalnerves for denervation. Some of the elements of the renal vascularsystem are omitted in FIG. 5C. In FIG. 5C, 102 is the kidney, 105 is theguiding catheter, 106 is main renal artery, 107 is balloon catheter, 301is abdominal aorta, and 502 extra-renal artery.

In one embodiment, the method for treatment of hypertension includesinserting a delivery catheter percutaneously into the renal arteryand/or extra-renal arteries adjacent to the nerves and nerve endings;using the delivery catheter to infuse the formulation described above tothe tissue of the body lumen adjacent to the nerves, wherein the amountof the formulation delivered is effective to injure the nerves and nerveendings, such as, for instance, by lowering blood pressure; and, lastly,withdrawing the delivery catheter from the body lumen.

In one embodiment, a balloon infusion catheter, for example as shown inFIGS. 3A-3B, 4A-4B, 7, 8A-8B, and 9A-9C, can be used for hypertensiontreatment. Examples of the pre-clinical trials with the embodiments aredescribed below.

In one example, a porcine animal weighing 47 kg was anesthetized withisoflurane, and one side of its renal artery was ablated with ethanolusing a balloon catheter while the contralateral renal artery served asa control. Using a standard renal access procedure, the balloon infusioncatheters were placed into the targeted renal arteries of the main andextra-renal branches in sequence over a guide wire. Upon reaching thetargeted ablation site, the balloon was inflated and absoluteethanol-mediated renal arterial chemical ablation took place via theexpandable infusion method. The balloon diameter was determinedaccording to renal angiograms, and a total of four catheters wereemployed. During the ablation treatment, the balloons were rapidlyinflated up to 6 to 8 atm with ethanol first, then ramped down to 0.5 to1 atm and maintained at the lower pressure for about 60 seconds. By theend of the treatment time, the balloon was deflated and withdrawn, orplaced into another artery site if required for the next treatment.

For a better clinical outcome, the balloon outer diameter (OD, thelarger diameter section) and the arterial inner diameter (ID) may existin a certain ratio. A slightly over-sized balloon OD to vessel ID can beused, such as

Balloon OD/Vessel ID=1.10 to 1.40; or=1.20 to 1.35.

Post-ablation renal angiograms were obtained to determine whether vesselspams, stenosis, or other abnormalities occurred. There were nosignificant renal arterial spasms during and after the balloon infusiontreatment.

The animal was euthanized two weeks after treatment, and renal tissuesamples were obtained from the cranial, middle, and caudal of the renalcortex to determine the renal tissue norepinephrine (NE) content usingknown HPLC methods. Norepinephrine is a neurotransmitter whose levelsserve as a standard measurement for renal denervation. Renal arteriesand surrounding tissues were collected for histopathologic evaluation aswell. Ethanol ablation of the renal artery resulted in a 72% reductionin renal norepinephrine reduction (NE content: control: 570 ng/g; renaldenervated, i.e. RDN: 160 ng/g), as shown in FIG. 12.

Not only was the NE content reduced after ethanol ablation, buthistopathologic evaluation also demonstrated renal nerve injury, asshown in FIG. 16, where nerves are pictured (black arrows) surrounded bymild fibrosis within the outer margins of the tunica adventitia.

To confirm results from the above study, a second study was conducted.The same infusion device and same study period (2-week chronic study) asdescribed above were used in this confirmation study.

Six porcine animals weighing 44 to 56 kg were divided into threetreatment sub-groups with two treated in the main renal artery, twotreated in the extra-renal branches, and two treated in both the mainrenal artery and the extra-renal branches. Again, for each animal, oneside of the renal arterial vessel(s) was (were) treated while thecontralateral served as a control. A standard renal access procedure wasperformed.

During the treatment, balloon size was determined according to theballoon OD/artery ID ratio that range from 1.20 to 1.35. These valuesprovided for better treatment effectiveness and minimal vessel injury byregulating over-dilatation. The inflation pressure used in this studyduring the rapid inflation cycle was 10 to 12 atm; the pressure was thenramped down to 0.5 to 1 atm, and the treatment was maintained at the lowpressure for 2 minutes at the main renal artery site and 1 minute in theextra-renal branch arteries. Renal angiograms showed no significantrenal arterial spasms during and after balloon infusion treatment in allof six porcine animals of this study.

Rena arterial ethanol ablation of the main renal artery alone resultedin an average norepinephrine (NE) reduction of about 40%. Extra-renalarterial branches ethanol ablation resulted in about an 8%norepinephrine reduction. Chemical ablation of the main renal artery andthe extra-renal arterial branches collectively resulted in more than a90% norepinephrine content reduction; cranial cortex norepinephrinereduction: 93.81%, 94.07%, 94.43% middle cortex tissue norepinephrinereduction: 91.98%, 92.19%, 93.20%, caudal cortex tissue norepinephrinereduction: 73.27%, 31.80%. 47.06%. This study demonstrated that both thequality of the balloon and degree of renal arterial tissue contactduring treatment contribute to high efficacy.

In addition to the reduction in NE, histopathologic evaluationdemonstrated renal nerve injury (as shown in FIG. 16), depicting bothlarge caliber perivascular nerves surrounded by fibrosis andinflammation and multi-focal degenerate and/or necrotic tissues.Circumferential effects were also observed. Overall, an average renalnerve injury value of 50% in the treated renal arteries was estimated.

In one embodiment, the catheter 10 (in FIG. 1) disclosed herein helpsregulate formulation flow and treatment dose throughout the treatmentwindow 30, as shown in FIG. 6. Balloons can be inflated through theirinflation lumen. The position, diameter, number and frequency of lateralapertures 31 results in the homogeneous filling of the treatment window30. FIG. 6 depicts a catheter positioned in a body lumen 5 having twolateral apertures 31 located within the treatment window 30 for deliveryof the therapeutic agent 3. Catheter tip 13, mark bands 23 a and 23 b,expandable balloons 20 and 21 are shown in FIG. 6. The lateral apertures31, as shown in FIG. 6, are in fluid communication with the inner lumen25. Lateral apertures 31 located within the treatment window 30 can bein communication with either the outer 24 or inner 25 lumen such thatthe formulation is delivered homogeneously to the treatment window 30.

In one embodiment, a cross-sectional view of the distal portion of thetri-balloon infusion catheter is depicted, as shown in FIG. 7. Thisinfusion device can provide homogeneous filling at the treatment site.The balloons in FIG. 7 are shown in an expanded state with two largerdiameter balloons, D1 and D3, at distal and proximal ends, and onesmaller diameter balloon (D2) in the middle. The combination of balloondiameters is determined by Equation 1 using a pre-defined ratio valueaccording to clinical dose requirement. The combination of balloonlengths depends on targeted vessel length and tortuousness.

One of the designs is for a four-lumen shaft that serves as an infusioncatheter. The four lumens can be assigned for wire (1), ballooninflation (1) and chemical treatment (2), for example, as shown inFIG. 1. Alternatively, a catheter can be designed to have more lumens toaccommodate more inflation lumens, where each balloon can he inflatedindependently.

Chemical treatment ports are located between the balloons on the shaft.The formulation infusion holes are located on the non-expandable shaftsection between the expandable balloon sections. During treatment, theformulation can be discharged between the balloons through the infusionhole to fill in the space created by the smaller diameter balloon. Thisis a non-expandable infusion method.

In one embodiment, optionally, the residual of the chemicalagent/formulation may be retrieved by vacuum technique on one of theinfusion holes following treatment. In this case, at least two treatmentlumens may be used: one for infusion and the other for vacuum. Theformulation infusion and vacuum holes are located on the non expandableshaft section between the expandable balloon sections.

The method can include flushing the body lumen with saline solution todilute the formulation. The flushing can occur after removing some ofthe formulation from the body lumen, or after removing none of theformulation from the body lumen. In addition to the withdrawal of excesstreatment agent, left-over agent can also be diluted with saline orwater to an ineffective concentration. Flushing with saline or water canbe performed using a catheter wire lumen, or one of the infusion lumens,or by other means. The method of use depends upon the site of protectionor treatment. If the distal portion of vessels requires protection fromthe chemical treatment, flushing can be performed via wire lumen.

In one embodiment, as shown in FIG. 8A, a new unconventional balloonattachment method can be applied. The new method includes placing theballoon waists inside balloon cones or bodies: this serves to overcomethe extra unwanted space which surrounds the smaller diameter balloonand is created by the balloon waist length and cone length, as shown inFIG. 7. Extra space confers no benefit for chemical treatment and maylead to overdose due to an inability to control therapeutic volume. Theformulation infusion and vacuum holes are located on the non-expandableshaft section between the expandable balloon sections.

To demonstrate the effectiveness of the new assembly method when extraspace is minimized, similar balloon diameter combinations were employed(FIG. 8A vs. FIG. 7). L(ii) represented in FIG. 8A is L(i) or L(ii). Inan expanded state, the cones of the adjacent balloons are now contactingeach other more intimately, thus minimizing the extra space. Again, theformulation is delivered between the balloons and will fill the spaceabove the small diameter balloon section area.

This new balloon assembly method can be described by the difference inballoon length before and after top assembly. Here, balloon length L(i)is defined as the length from the transition point of the distalwaist/cone to that of the proximal cone/waist prior to shaft assembly;and balloon length L(ii) is defined as the length from the transitionpoint of the distal waist/cone to that of the proximal cone/waistfollowing shaft assembly. In this new assembly method, balloon waistswere placed inside cones, or in some cases inside the balloon body aswell if the cone length was short. The relationships between L(i) andt(ii) are:

(1). L(i)=L(ii.); if the balloon is assembled using a conventionalmethod.(2), L(i)>L(ii); if the balloon is assembled using the new method.Depending upon the length of the balloon cone, this new infusioncatheter would have the cone/waist transition point at least at 25%inside the cone, or at 50 or 100% inside the cone, or partially orcompletely inside the balloon body.

For illustration purposes, consider an example involving an 8×20 mmballoon with a 5 mm cone length on both the distal and proximal sides.In this case, L(i)=body length+distal cone length+proximal conelength=20+5+5=30 mm. Situation 1: if the cone/waist transition pointsare placed 50% inside the cone, then L(ii)=20+2.5+2.5=25 mm; L(i)>L(ii).Situation 2: if the cone/waist transition points are placed 100% insidethe cone or at the transition line of the cone/body, thenL(ii)=20+0+0=20 mm; L(i)>L(ii). If the waist is further placed inside,then it would be situated inside the balloon body.

In the multiple balloon assembly on the catheter, the balloons havingthe same L(i) could also have the same L(ii) or a different one.

In another embodiment, a regular cone-shaped balloon can be used forthis catheter. A round or radius cone balloon may also be used, however,because of its short cone length and potential for more contact surfacearea between adjacent cones.

In one embodiment, as shown in FIG. 8B, balloons can be attached ontothe shaft by placing the balloon waists inside or partially inside thebaboon body with inverted balloon waists. The inverted balloon waistswould make the balloon cone more naturally rounded and would allow formore contact surface area between the cones; in addition, the waistscould more easily be placed inside the balloon body.

In one embodiment, when a narrow treatment band or shorter overallballoon length is required, a double-balloon combination is used. FIG.9A displays the two balloons having contacted adjacent cones in anexpanded state. A chemical agent could be delivered through the deliveryport on the shaft located between the two balloons. The formulationinfusion and/or vacuum holes are located on the non-expendable shaftsection between the expandable balloon sections. The chemical agentcould remain in the middle narrow section of the two balloons duringtreatment. Optionally, the additional port could he available forflushing or vacuuming purposes. The two balloons on the catheter couldalso have their own inflation lumen, and, thus, could be inflatedindependently.

In another embodiment, shown in FIGS. 9B-9C, a dual-diameter balloon canbe used for the infusion catheter to achieve a wider treatment lengthdespite a shorter overall balloon length. This balloon has two diametersthat are smaller on one side relative to the other. Employing the sameassembly technique as in the three-balloon arrangement, thedual-diameter balloons are attached on the shaft with the smallerdiameter sides assembled head-to-head to form a smaller diameter middlesection. The two ends of the large diameter sections confine thechemical agent primarily to the middle smaller diameter section toachieve a controlled volume delivery. The formulation infusion and/orvacuum holes are located on the non-expandable shaft section between theexpandable balloon sections. Again, the formulation is delivered throughthe infusion holes on the non-expandable shaft section between the twoexpandable balloon sections.

One of the dual-diameter balloons is the tapered balloon shown in FIG.9B. This two-balloon configuration has smaller diameter ends located inthe middle of the two balloons facing head-to-head to each other. Theresulting overall diameter of the middle section is smaller than that ofthe ends.

Another dual-diameter balloon is assembled from two-stage balloons, asshown in FIG. 9C. There are two distinct diameters in one balloon, i.e.,one side of the balloon is bigger than the other; and there is an abruptdiameter change between the two diameters. Two-stage balloons can beassembled with the smaller diameter sides facing each other (FIG. 9C)and forming the middle of the overall balloon. The stage balloon canprovide a wider treatment length despite having the same overall balloonlength as in FIG. 9B.

FIGS. 10A and 10B illustrate balloon infusion catheter 365 is positionedin a gastric artery 360 or a hepatic artery 320. Various arteriessurrounding the liver and stomach as well as the various nerve systemsthat innervate the liver and stomach and their surrounding organs andtissues are shown in FIGS. 10A and 10B. The arteries surrounding theliver and stomach include the abdominal aorta 305, the celiac artery310, the common 315 and proper hepatic arteries 320, the gastroduodenalartery 322, the right 325 and left hepatic arteries 330, the splenicartery 335 and esophageal branches 361. The various nerves thatinnervate the liver and stomach and their surrounding organs and tissuesinclude the celiac 340 and hepatic plexuses 345. Blood supply to theliver is pumped from the heart into the aorta and then down through theabdominal aorta 305 and into the celiac artery 310. From the celiacartery 310, blood travels through the common hepatic artery 315, intothe proper hepatic artery 320, then into the liver through the right 325and left hepatic arteries 330. The common hepatic artery 315 branchesoff from the celiac trunk and gives rise to gastroduodenal arteries. Thenerves innervating the liver include the celiac plexus 340 and thehepatic plexus 345. The celiac plexus 340 wraps around the celiac artery310 and continues into the hepatic plexus 345, which wraps around theproper 320 and common hepatic arteries 315, and/or continues on to theright 325 and left hepatic arteries 330. In some anatomies, the celiac340 and hepatic plexuses 345 adhere tightly to the walls of thearteries, supplying the liver with blood, thereby renderingintra-to-extra-vascular neuromodulation particularly advantageous. Inseveral embodiments, the media thickness of vessels (e.g., the hepaticartery) ranges from about 0.1 cm to about 0.25 cm. In some embodiments,the formulations may be delivered to the inner wall of the target vesselor target nerves. Intravascular delivery may be employed, because thenerves tightly adhere to the outer walls of the arteries, thus supplyingblood to the liver (e.g. in the case of the hepatic artery branches).

The arteries surrounding the stomach include the abdominal aorta 305,the celiac artery 310, the right 355 and left gastric arteries 360, andthe esophageal branches 361. Blood supply to the stomach is pumped fromthe heart into the aorta and then down through the abdominal aorta 305and into the celiac artery 310. From the celiac artery 310, bloodtravels through the right gastric artery 355 and left gastric artery360, the esophageal branches 361, and into the stomach.

With continued reference to FIGS. 10A and 10B, the hepatic plexus 345 isthe largest offset from the celiac plexus 340. The hepatic plexus 345 isbelieved to primarily carry afferent and efferent sympathetic nervefibers, the stimulation of which can increase blood glucose levels by anumber of mechanisms. For example, stimulation of sympathetic nervefibers in the hepatic plexus 345 can increase blood glucose levels byenhancing hepatic glucose production, or by reducing hepatic glucoseuptake. Disruption of sympathetic nerve signaling in the hepatic plexus345 can, therefore, alter levels of blood glucose.

In one embodiment, FIG. 10B depicts a schematic view of a balloondelivery catheter positioned within the hepatic artery for treatment ofdiabetes. In another embodiment, FIG. 10A depicts a schematic view of aballoon delivery catheter positioned within the left gastric artery fortreatment of obesity and diabetes.

Certain embodiments of the invention include delivering a vapor orliquid formulation to the segment of the body lumen at a specificdelivery rate for a pre-determined duration. The formulation may beheated to at least 80° C., for example, 100° C. or 150° C., prior todelivery. The catheter materials, specifically the balloon and shafts,should be functional at the above temperatures, as such materials aremade to withstand high temperatures. In certain embodiments, deliveredvapors can undergo a phase change to liquid, resulting in a release ofenergy, which is transferred to the tissue.

In certain embodiments, for example, the safe and effective dose fortreating the tissue ranges from about 2 cal/g to about 150 cal/g., orfrom about 5 cal/g to about 100 cal/g, and the energy flow rate of thedelivery system ranges from about 2 cal/g to about 500 cal/sec, or fromabout 5 cal/sec to about 150 cal/sec. In one embodiment, the formulationgenerator creates a vapor or liquid formulation, with a pressure thatranges from about 2 psi to 200 psi and a temperature that ranges fromabout 20° C. to 150° C., or from about 50° C. to 120° C.

A safe and effective amount of formulation and/or energy should beapplied in order to satisfactorily injure tissues. In general, the doseamount correlates with the degree of injury to the tissue.

In some embodiments, an effective dose of energy ranges from about 1 toabout 100 cal/g and/or an effective formulation dose ranges from 0.2microliters to 200 milliliters. These dosing limitations may vary asother delivery parameters (e.g., delivery rate or duration, etc.) mayedit for different doses to accomplish the ultimate injury benefit.

Following dose determination, the total amount of energy (cals) orformulation (mls) applied via a delivery system should be determined.This value is calculated by multiplying dose (cal/g) by the amount oftissue to be treated (grams).

The delivery/flow rate, or the rate at which the delivery systemdelivers the formulation, generally determines the duration offormulation. For example, at a delivery rate of 30 cals/sec, a treatmentduration of 10 seconds would be necessary to deliver 300 calories. Thedelivery rate generally ranges from about 2 to about 200 cals/sec.Again, these limitations are not definite and can change depending ontreatment and/or delivery parameters.

Treatment times can vary depending on the volume of the tissue to betreated, and the intended degree of injury to the target tissue.Treatment times can vary from about 2 seconds to about 60 minutes. Insome embodiments for inducing injury to relieve symptoms, the safe andeffective treatment time ranges from about 4 seconds to about 30minutes.

The delivery rate can be set by regulating the delivery system. Once theuser establishes the delivery rate, formulation resources will determinethe amount of pressure necessary to deliver the vapor or liquid at thedesired rate. Changing the delivery rate setting will cause theformulation generator to adjust the amount of pressure delivered. Thepressure in the vapor generator can range from about 5 psi to about 200psi, or from about 10 psi to about 50 psi.

In one embodiment, the method for treatment of hypertension includesinserting a delivery catheter percutaneously into the renal arteryadjacent to the nerves; using the catheter to infuse the formulationdescribed above and/or heat to the tissue of the body lumen adjacent tothe nerves, wherein the amount of the formulation and/or heat deliveredis effective to injure or damage the nerves, such as, for instance, bylowering blood pressure; and, lastly, withdrawing the delivery catheterfrom the body lumen. The purpose of the heat is to enhance theinjury/damage effect by accelerating the reaction rate between theformulation and nerves. Potential formulations include gases, vapors,liquids, solutions, emulsions, and suspensions of one or moreingredients. If the formulation includes vapors of one or moreingredients, the heat may be generated by condensation of the vaporsinto liquids in the tissue. If the formulation includes liquids orsolutions, the heat may he transferred from the high temperatureformulations that exceed body temperature. The formulation temperaturemay range from −40° C. to 140° C. from −30° C. to 100° C., or from −20°C. to 80° C. The temperature of the treated tissue adjacent to thenerves may he lower than the formulation temperature and higher thanbody temperature. The temperature of the treated tissue adjacent to thenerves may range from −40° C. to 100° C., from −30° C. to 90° C., orfrom −20° C. to 80° C. The formulation infusion pressure may range from0.1 atm to 14 atm, from 3 atm to 10 atm, or from 4 atm to 8 atm.

In one embodiment, the method for treatment of asthma includes insertinga delivery catheter into the airways adjacent to the nerves; using thecatheter to infuse the formulation described above and/or heat to thetissue of the airway adjacent to the nerves, wherein the amount of theformulation and/or heat delivered is effective to injure or damage thenerves, such as, for instance, by relieving shortness of breath; and,lastly, withdrawing the delivery catheter from the body lumen. Thepurpose of the heat is to enhance the injury/damage effect byaccelerating the reaction rate between the formulation and nerves.Potential formulations include gases, vapors, liquids, solutions,emulsions, and suspensions of one or more ingredients. If theformulation includes vapors of one or more ingredients, the heat may begenerated by condensation of the vapors into liquids in the tissue. Ifthe formulation includes liquids or solutions, the heat may betransferred from the high temperature formulations that exceed bodytemperature. The liquid formulation temperature may range from −40° C.to 140° C., from −30° C. to 100° C., or from −20° C. to 80° C. Thetemperature of the treated tissue adjacent to the nerves may be lowerthan the formulation temperature and higher than body temperature. Thetemperature of the treated tissue adjacent to the nerves may range from−40° C. to 100° C., from −30° C. to 90° C. or from −20° C. to 80° C. Theformulation infusion pressure may range from 0.1 atm to 14 atm, from 3atm to 10 atm, or from 4 atm to 8 atm.

In one embodiment, the method for treatment of a COPD includes insertinga delivery catheter into the airway adjacent to the nerves; using thecatheter to infuse the formulation described above and/or heat to thetissue of the body lumen adjacent to the nerves, wherein the amount ofthe formulation and/or heat delivered is effective to injure or damagethe nerves, such as, for instance, by relieving COPD symptoms; and,lastly, withdrawing the delivery catheter from the airway. The purposeof the heat is to enhance the injury/damage effect by accelerating thereaction rate between the formulation and nerves. Potential formulationsinclude gases, vapors, liquids, solutions, emulsions, and suspensions ofone or more formulations. If the formulation includes vapors of one ormore ingredients, the heat may be generated by condensation of thevapors into liquids. If the formulation includes liquids or solutions,the heat may he transferred from the high temperature formulations thatexceed body temperature. The formulation temperature may range from −40°C. to 140° C. from −30° C. to 100° C., or from −20° C. to 80° C. Thetemperature of the treated tissue adjacent to the nerves may be lowerthan the formulation temperature and higher than body temperature. Thetemperature of the treated tissue adjacent to the nerves may range from−40° C. to 100° C., from −30° C. to 90° C., or from −20° C. to 80° C.The formulation infusion pressure and/or the balloon inflation pressuremay range from 0.1 atm to 14 atm, from 3 atm to 10 atm, or from 4 atm to8 atm.

In one embodiment, the method for treatment of diabetes includesinserting a delivery catheter percutaneously into the hepatic arteriesadjacent to the nerves, specifically the hepatic celiac artery, properhepatic arteries, and the left and right hepatic arteries; using thecatheter to infuse the formulation described above and/or heat to thetissue of the body lumen adjacent to the nerves, wherein the amount ofthe formulation and/or heat delivered is effective to injure or damagethe nerves, such as, for instance, by lowering glucose level; and,lastly, withdrawing the delivery catheter from the body lumen. Thepurpose of the heat is to enhance the injury/damage effect byaccelerating the reaction rate between the formulation and nerves.Potential formulations include gases, vapors, liquids, solutions,emulsions, and suspensions of one or more ingredients. If theformulation includes vapors of one or more ingredients, the heat may begenerated by condensation of the vapors into liquids in the tissue. Ifthe formulation includes liquids or solutions, the heat may betransferred from the high temperature formulations that exceed bodytemperature. The formulation temperature may range from −40° C. to 140°C., from −30° C. to 100° C., or from −20° C. to 80° C. The temperatureof the treated tissue adjacent to the nerves may be lower than theformulation temperature and higher than body temperature. Thetemperature of the treated tissue adjacent to the nerves may range from−40° C. to 100° C. from −30° C. to 90° C. or from −20° C. to 80° C. Theformulation infusion pressure and/or the balloon inflation pressure mayrange from 0.1 atm to 14 atm, from 3 atm to 10 atm, or from 4 atm to 8atm.

In one embodiment, the method for treatment of obesity and diabetesincludes inserting a delivery catheter into the left and/or rightgastric arteries adjacent to the stomach and esophageal nerves; usingthe catheter to infuse the formulation described above and/or heat tothe tissue of the gastric arteries adjacent to the nerves, wherein theamount of the formulation and/or heat delivered is effective to injureor damage the nerves such as, for instance, by lowering body weight;and, lastly, withdrawing the delivery catheter from the gastricarteries. Potential formulations include gases, vapors, liquids,solutions, emulsions, and suspensions of one or more ingredients. If theformulation includes vapors of one or more ingredients, the heat may begenerated by condensation of the vapors into liquids. If the formulationincludes liquids or solutions, the heat may be transferred from the hightemperature formulations that exceed body temperature. The liquidformulation temperature may range from −40° C. to 140° C., from −30° C.to 100° C., or from −20° C., to 80° C. The temperature of the treatedtissue adjacent to the nerves may be lower than the formulationtemperature and higher than body temperature. The temperature of thetreated tissue adjacent to the nerves may range from −40° C. to 100° C.,from −30° C. to 90° C., or from −20° C. to 80° C. The formulationinfusion pressure and/or the balloon inflation pressure may range from0.1 atm to 14 atm, from 3 atm to 10 atm, or from 4 atm to 8 atm.

In one embodiment, the method for treatment of obesity and diabetesincludes inserting a delivery catheter percutaneously into the hepaticarteries adjacent to the nerves, specifically the hepatic celiac artery,the proper hepatic arteries, and the left and right hepatic arteries;using the catheter to infuse the formulation described above and/or heatto the tissue of the hepatic arteries adjacent to the nerves;withdrawing the delivery catheter from the hepatic arteries; inserting adelivery catheter into the left and/or right gastric arteries adjacentto the stomach and esophageal nerves; using the catheter to infuse theformulation described above and/or heat to the tissue of the gastricarteries adjacent to the nerves, wherein the amount of the formulationand/or heat delivered is effective to injure or damage the nerves, suchas, for instance, by lowering body weight and glucose level; and,lastly, withdrawing the delivery catheter from the gastric arteries.Potential formulations include gases, vapors, liquids, solutions,emulsions, and suspensions of one or more ingredients. If theformulation includes vapors of one or more ingredients, the heat may begenerated by condensation of the vapors into liquids. If the formulationincludes liquids or solutions, the heat may be transferred from the hightemperature formulations that exceed body temperature. The liquidformulation temperature may range from −40° C. to 140° C., from −30° C.to 100° C., or from −20° C. to 80° C. The temperature of the treatedtissue adjacent to the nerves may be lower than the formulationtemperature and higher than body temperature. The temperature of thetreated tissue adjacent to the nerves may range from −40° C. to 100° C.,from −30° C. to 90° C., or from −20° C. to 80° C. The formulationinfusion pressure and/or the balloon inflation pressure may range from0.1 atm to 14 atm, from 3 atm to 10 atm, or from 4 atm to 8 atm.

In one embodiment, the method for treatment of obesity includesinserting a delivery catheter into the digestive lumen adjacent to thenerves; using the catheter to infuse the formulation described aboveand/or heat to the tissue of the digestive lumen, wherein the amount ofthe formulation and/or heat delivered is effective to injure or damagethe tissue, such as, for instance, by lowering body weight; and, lastly,withdrawing the delivery catheter from the digestive lumen. Potentialdigestive lumens for this embodiment include the esophagus, the stomach,the duodenum, the jejunum, the small and large intestines, and thecolon. The purpose of the heat is to enhance the injury/damage effect byaccelerating the reaction rate between the formulations and nerves.Potential formulations include gases, vapors, liquids, solutions,emulsions, and suspensions of one or more ingredients. If theformulation includes vapors of one or more ingredients, the heat may begenerated by condensation of the vapors into liquids. If the formulationincludes liquids or solutions, the heat may be transferred from the hightemperature formulations that exceed body temperature. The liquidformulation temperature may range from −40° C. to 140° C., from −30° C.to 100° C., or from −20° C. to 80° C. The temperature of the treatedtissue adjacent to the nerves may be lower than the formulationtemperature and higher than body temperature. The temperature of thetreated tissue adjacent to the nerves may range from −40° C. to 100° C.,from −30° C. to 90° C., or from −20° C. to 80° C.

In one embodiment, the method for treatment of obesity and diabetesincludes inserting a delivery catheter into the left and/or rightgastric arteries adjacent to the stomach and esophageal nerves; usingthe catheter to infuse the formulation described above and/or heat tothe tissue of the gastric arteries adjacent to the nerves, wherein theamount of the formulation and/or heat delivered is effective to injureor damage the nerves, such as, for instance, by lowering body weight;and, lastly, withdrawing the delivery catheter from the gastricarteries. Potential formulations include gases, vapors, liquids,solutions, emulsions, and suspensions of one or more ingredients. If theformulation includes vapors of one or more ingredients, the heat may begenerated by condensation of the vapors into liquids. If the formulationincludes liquids or solutions, the heat may be transferred from the hightemperature formulations that exceed body temperature. The liquidformulation temperature may range from −40° C. to 140° C., from −30° C.to 100° C., or from −20° C. to 80° C. The temperature of the treatedtissue adjacent to the nerves may be lower than the formulationtemperature and higher than body temperature. The temperature of thetreated tissue adjacent to the nerves may range from −40° C. to 100° C.,from −30° C. to 90° C., or from −20° C. to 80° C.

In one embodiment, the method for treatment of obesity and/or diabetesand/or nonalcoholic fatty liver disease includes inserting a deliverycatheter orally via the mouth, esophagus and stomach into the duodenumand: or jejunum; using the catheter to infuse the formulation describedabove and/or heat to the surface tissue of the duodenum and/or jejunumfor 1-30 minutes, wherein the amount of the formulation and/or heatdelivered is effective to injure or damage the surface, the tissue andthe nerves of the body lumen, such as the duodenum or, jejunum, forinstance, by lowering body weight and glucose level; optionally removingor withdrawing the formulation; and, lastly, withdrawing the deliverycatheter from the digestive lumen, such as the duodenum or jejunum.Potential formulations include gases, vapors, liquids, solutions,emulsions, and suspensions of one or more ingredients. If theformulation includes vapors of one or more ingredients, the heat can begenerated by condensation of the vapors into liquids. If the formulationincludes liquids or solutions, the heat can be transferred from the hightemperature formulations that exceed body temperature. The formulationinfusion pressure and/or the balloon inflation pressure may range from0.1 atm to 14 atm, from 3 atm to 10 atm, or from 4 atm to 8 atm. Theliquid formulation temperature may range from −40° C. to 140° C., from−30° C. to 100° C., or from −20° C. to 80° C. The temperature of thetreated tissue, which, in this case is the surface tissue, may be lowerthan the temperature of the formulation and higher than bodytemperature. The temperature of the treated tissue may range from −40°C. to 100° C., from −0° C. to 90° C., from 36° C. to 80° C., or from 60°C. to 80° C. Treatment entails modifying the surface of the duodenum orjejunum. Therapeutic benefits such as lowering of body weight, glucoselevels, and/or HbA1c (A1C) levels, depend on formulation dose andtemperature, length of treatment period, and the surface area andthickness of the treated duodenum. For safety reasons, perforation ofthe duodenum is not encouraged. Treating the surface modifies themorphology, the nerves, and food absorption capacity of the duodenum.

In one embodiment, the method for treatment of obesity and/or diabetesand/or nonalcoholic fatty liver disease includes non-invasivelyinserting an infusion catheter orally via the mouth, esophagus andstomach into the duodenum and/or jejunum; using the catheter to infusechemical agents to the surface tissue of the duodenum and/or jejunum for1-10 minutes, wherein the amount of the chemical agent delivered iseffective to injure or damage the surface, the tissue and the nerves ofthe body lumen, such as the duodenum or jejunum, for instance, bylowering body weight and glucose level; optionally removing orwithdrawing the agents; and, lastly, withdrawing the delivery catheterfrom the digestive lumen, such as the duodenum or jejunum. The chemicalagent includes the formulation of chemical agents and/or absoluteethanol. Below are descriptions of pre-clinical trials for the treatmentof obesity and/or diabetes.

All infusion catheters in the embodiments described above are applicableto the following studies. For instance, in one study, the 2-3-groovedumbbell-type balloons with 4-holes per groove were used for thetreatment of obesity and/or diabetes. Balloon diameters and lengthsranged from 12 to 15 mm and from 55 to 80 mm, respectively. The studywas conducted according to the procedure described above. Two juvenileYorkshire cross pigs (each weighing about 9 kg) were anesthetized withisoflurane. An infusion balloon catheter was inserted via the mouth,stomach and pylorus into the duodenum under guidance of a pediatricendoscope and fluoroscope. The ligament of treitz was used as theanatomical mark for the distal end of the duodenum. Upon delivery of theinfusion balloon catheter to the duodenum, 1.5 to 2.0 ml of absoluteethanol was injected after rapid pre-inflation of the balloon up to 1.5atm. Balloon pressure was then held at 0.5 atm or less for 1 to 2 min.The treatment agent played dual roles in this procedure: (1) inflationof the balloon and (2) delivery of the chemical to the target vesseltissue through the holes on the balloon wall. After treatment, theballoon was partially deflated and pulled back to a defined distance toavoid overlapping with the next treatment location. Treatment was thenrepeated. The bile duct was not treated. The animal was euthanized 2hours after treatment. The duodenal tissue was examined and suspended intriphenyl tetrazolium chloride (TTC) solution for 30 minutes. Followingchemical treatment, the necrotized tissue may display white-coloredspots.

The chemical agents used in the above described study were pure aceticacid and absolute ethanol. Treatment efficacy was clearly demonstratedin the TIC-stained duodenal tissues from both treated animals, aswhite-colored spots were localized to chemically-ablated regions.

Following the success of the above acute study, a chronic study wasconducted to demonstrate the clinical benefits of the treatment. Thestudy included seven pigs of similar weight as in the acute study above.Three of the seven pigs were treated with absolute ethanol, three withacetic acid, and one sham pig with saline. The same procedure asdescribed in the previous acute study was employed for treatment withabsolute ethanol. As before, after the infusion balloon catheter reachedthe duodenum, the balloon was rapidly pre-inflated with absolute ethanolup to a pressure of 1.5 atm; about an additional 1.5 ml to 2.0 ml ofethanol was next injected through the balloon wall into the duodenum,and pressure was then held for 2 min at 0.5 atm or below. Once thetreatment period ended, the treated duodenal section was then flushedwith about 10 ml of water using the endoscope.

Treatment with acetic acid proceeded similarly to that with absoluteethanol. As before, the pig duodena were treated, this time at a dose of0.5 ml for 1 minute. After each treatment, balloons were partiallydeflated and pulled back to a pre-defined distance to avoid overlappingtreatment with the next treatment location. Treatment was then repeated.The bile duct was not treated. Animals were recovered for chronicobservation and evaluation.

Pigs that underwent duodenal treatment with acetic acid were euthanizedabout five weeks after treatment. The animals were determined to behealthy following clinical and pathological evaluation. As demonstratedin FIG. 13, treatment of the duodenum with acetic acid did not havesignificant weight difference in comparison with that of the shamanimals. Glucose levels fluctuated and were inconclusive.

Pigs that underwent duodenal treatment with absolute ethanol wereeuthanized about eight weeks after treatment. The animals weredetermined to be healthy following clinical and pathology evaluation. Asdemonstrated in FIG. 14, treatment of the duodenum with absolute ethanolresulted in less animal weigh increases in comparing with the shamanimal. Glucose levels were inconclusive.

In one embodiment, the method for treatment of Barrett's esophagusdisease includes an infusion balloon device, a procedure, and a chemicalagent. In this method, a balloon infusion catheter is insertednon-invasively via the mouth into the esophagus under pediatricendoscopic guidance. 15 mm balloons are typically used at a lengthranging from 55 to 80 mm, with 3 grooves in the middle section and 4micro-holes per groove for chemical infusion. Once balloons localize tothe target esophagus, they are rapidly pre-inflated to full size at apressure up to 1.5 atm. Examples of doses delivered are as follows: (1)for treatment with absolute ethanol, 1.5 ml are delivered at the distalportion of the esophagus for 4 min and at the proximal portion for 2min: (2) for treatment with acetic acid, 0.5 ml are delivered at thedistal portion of the esophagus for 2 min and at the proximal portionfor 1 min. Once the treatment period ends, treated sites are flushedwith about 10 ml of water using an endoscope channel. Following eachtreatment, balloons are partially deflated and moved to other locationsfor additional treatments.

Using the above described procedure, a chronic study was conducted withseven juvenile Yorkshire cross pigs. Three of the seven pigs weretreated with absolute ethanol, three with acetic acid, and a sham withsaline. Endoscopic examinations were performed before and aftertreatment. Animals were recovered for chronic observation andevaluation. Animals were also endoscopically examined after two weeks oftreatment and were reexamined and euthanized after four weeks. Effectsof treatment were assessed by the endoscopic exam. In aceticacid-treated esophageal sections, severe stricture phenomena wereobserved. Histopathological analysis of treated sections demonstratedepithelial thickening and complete epithelization except for in theacetic acid-treated group, where the epithelial layer was, at times,absent.

The above pre-clinical findings demonstrate that ethanol treatment iseffective and safe. Acetic acid treatment, on the other hand, led tosevere narrowing and stricture in the treated esophagus. In addition, nodifference in weight change was observed in duodenal-treated animalscompared with untreated animals. It is well known that acid erodes anddamages esophageal linings; acetic acid produced lesions in the duodenalwall following topical application. These observations indicate thatacetic acid may not be suitable for duodena and esophageal treatment.

In one embodiment, the method for treatment of urological diseasesand/or benign prostate hyperplasia (BPH) includes inserting a deliverycatheter into the urological lumen; using the catheter to infuse theformulation described above and/or heat to the lumen of a urologicaltissue, e.g. the prostate, urethra, and ureter, wherein the amount ofthe formulation and/or heat delivered is effective to injure or damagethe tissue, such as, for instance, by controlling the flow of urine;and, lastly, withdrawing the delivery catheter from the urologicallumen. The purpose of the heat is to enhance the injury/damage effect byaccelerating the reaction rate between the formulation and nerves. Theformulations include one of gases, vapors, liquids, solutions,emulsions, and suspensions of one or more ingredients. If theformulation includes vapors of one or more ingredients, the heat can begenerated by condensation of the vapors into liquids. If the formulationincludes liquids or solutions, the heat can be transferred from hightemperature formulations that exceed body temperature. The liquidformulation temperature may range from −40° C. to 140° C., from −30° C.to 100° C., or from −20° C. to 80° C. The temperature of the treatedtissue adjacent to the nerves may be lower than the formulationtemperature and higher than body temperature. The temperature of thetreated tissue adjacent to the nerves may range from −40° C. to 100° C.,from −30′'C. to 90° C. or from −20° C. to 80° C. The formulationinfusion pressure and/or the balloon inflation pressure may range from0.1 atm to 14 atm, from 3 atm to 10 atm, or from 4 atm to 8 atm.

In one embodiment, the method for treatment of cancers or tumorsincludes inserting a needle or needle-based catheter percutaneously ortransorally into the cancers or tumors under imaged guide; using thecatheter to infuse the formulation described above and/or heat to thecancer tissues of the human body, wherein the amount of the formulationand/or heat delivered is effective to injure, damage or eliminate thecancer tissues, such as, for instance, by shrinking or eliminating thetumors; and, lastly, withdrawing the delivery catheter from the body.Potential imaging guides include ultrasound, X-ray, CT scan, NMRimaging, and scopes. Relevant cancers include adrenal, bladder,cervical, colon, esophageal, gallbladder, kidney, liver, lung, ovarian,pancreatic, prostatic, rectal, stomach, and uterine. The purpose of theheat is to enhance the injury/damage/elimination effect by acceleratingthe reaction rate between the formulation and cancer tissues. Theformulations include one of gases, vapors, liquids, solutions,emulsions, and suspensions of one or more ingredients. If theformulation includes vapors of one or more ingredients, the heat may begenerated by condensation of the vapors into liquids in the tissue. Ifthe formulation includes liquids or solutions, the heat may betransferred from the high temperature formulations that exceed bodytemperature. The formulation temperature may range from −40° C. to 140°C. from −30° C. to 100° C., or from −20° C. to 80° C. The temperature ofthe treated tissue may be lower than the formulation temperature andhigher than body temperature. The temperature of the treated tissue mayrange from −40° C. to 100° C., from −30° C. to 90° C., or from −20° C.to 80° C.

Additional Embodiments

The following exemplary embodiments are provided, the numbering of whichis not to be construed as designating levels of importance:

Embodiment 1 provides a method for treating a disease, the methodcomprising:

a) inserting a delivery catheter into a body lumen;

b) infusing a formulation into a diseased tissue in the body lumen,wherein an amount of the formulation delivered to the body lumen iseffective to injure or damage the diseased tissue to relieve diseasesymptoms;

c) optionally removing the formulation from the body lumen; and

d) withdrawing the delivery catheter from the body lumen.

Embodiment 2 provides the method according to Embodiment 1, wherein thedisease is chosen from hypertension, pulmonary hypertension, diabetes,obesity, heart failure, end-stage renal disease, a digestive disease,nonalcoholic fatty liver disease, benign prostate hyperplasia, cancers,tumors, pain, asthma and chronic obstructive pulmonary disease (COPD).

Embodiment 3 provides the method according to Embodiment 2, whereincancers are chosen from adrenal, bladder, cervical, colon, esophageal,gallbladder, kidney, liver, lung, ovarian, pancreatic, prostatic,rectal, stomach, duodenum, jejunum, and uterine.

Embodiment 4 provides the method according to any one of Embodiments1-3, wherein the body lumen is chosen from a renal artery, a pulmonaryartery, a vascular lumen, a celiac artery, a common hepatic artery, aproper hepatic artery, a gastroduodenal artery, a right hepatic artery,a left hepatic artery, asplenic artery, a right gastric artery, aloftgastric artery, a nonvascular lumen, an airway, a sinus, an esophagus, arespiratory lumen, a digestive lumen, a stomach, a duodenum, a jejunum,a prostate, a urethra, a ureter, and/or a urological lumen.

Embodiment 5 provides the method according to any one of Embodiments1-4, wherein the formulation consists essentially of ethanol.

Embodiment 6 provides the method according to any one of Embodiments1-5, wherein the formulation consists of ethanol.

Embodiment 7 provides the method according to any one of Embodiments1-6, wherein the formulation comprises a gas, vapor, liquid, solution,emulsion, or suspensions of one or more ingredients.

Embodiment 8 provides the method according to Embodiment 7, wherein, ifthe formulation comprises a vapor of one or more ingredients, heat isgenerated by condensation of the vapor into liquid.

Embodiment 9 provides the method according to any one of Embodiments1-8, wherein, if the formulation comprises a liquid or solution, heat istransferred from the formulation to the diseased tissue.

Embodiment 10 provides the method according to any one of Embodiments1-9, wherein, if the formulation comprises an emulsion or a suspension,heat is transferred from the formulation to the diseased tissue.

Embodiment 11 provides the method according to any one of Embodiments1-10, wherein the formulation is at a temperature ranging from 40° C. to140° C.

Embodiment 12 provides the method according to any one of Embodiments1-11, wherein the formulation is at a temperature ranging from 0° C. to140° C.

Embodiment 13 provides the method according to any one of Embodiments1-12, wherein the formulation is at a temperature ranging from −40° C.to 0° C.

Embodiment 14 provides the method according to any one of Embodiments1-13, wherein the formulation is at a temperature equal to roomtemperature.

Embodiment 15 provides the method according to any one of Embodiments1-14, wherein the temperature of the diseased tissue is lower than thetemperature of the formulation.

Embodiment 16 provides the method according to any one of Embodiments1-15, wherein the temperature of the diseased tissue is higher than thetemperature of the formulation.

Embodiment 17 provides the method according to any one of Embodiments1-16, wherein pressure of the formulation during infusion ranges from0.1 atm to 14 atm.

Embodiment 18 provides the method according to any one of Embodiments1-17, wherein the diseased tissue is at a temperature ranging from −40°C. to 100° C.

Embodiment 19 provides the method according to any one of Embodiments1-18, wherein the diseased tissue is at a temperature ranging from −40°C. to 0° C.

Embodiment 20 provides the method according to any one of Embodiments1-19, wherein the diseased tissue is at a temperature equal to bodytemperature.

Embodiment 21 provides the method according to any one of Embodiments1-20, wherein pressure of the formulation during infusion ranges fromabout 2 psi to 200 psi at a temperature ranging from about −40° C. to150° C.

Embodiment 22 provides the method according to any one of Embodiments1-21, wherein an amount of the formulation infused into the diseasedtissue ranges from 0.2 microliters to 200 milliliters.

Embodiment 23 provides the method according to any one of Embodiments1-22, wherein the method comprises inserting the delivery catheter intothe body lumen for about 2 seconds to about 60 minutes.

Embodiment 24 provides the method according to any one of Embodiments1-23, wherein the method delivers an amount of heat or energy rangingfrom about 2 cal/g to about 150 cal/g to the diseased tissue.

Embodiment 25 provides the method according to any one of Embodiments1-24, wherein the delivery catheter is chosen from a needle orneedle-based delivery catheter, a single balloon delivery catheter, adouble balloon delivery catheter, an infusion catheter, a ballooninfusion catheter, a balloon catheter, a dumbbell balloon infusioncatheter, and combinations thereof.

Embodiment 26 provides the method according to Embodiment 25, whereinthe delivery catheter is inflated at a pressure ranging from 0.1 atm to14 atm.

Embodiment 27 provides the method according to any one of Embodiments1-26, wherein the formulation comprises one or more ingredients chosenfrom water, saline, hypertonic saline, phenol, methanol, ethanol,absolute alcohol, isopropanol, propanol, butanol, isobutanol, ethyleneglycol, glycerol, acetic acid, lactic acid, propyl isopropyl iodide,ethyl iodide, methyl acetate, ethyl acetate, ethyl nitrate, isopropylacetate, ethyl lactate, lipiodol, urea, and derivatives and combinationsthereof.

Embodiment 28 provides the method according to any one of Embodiments1-27, wherein the formulation comprises a gas or vapor chosen fromoxygen, nitrogen, helium, argon, air, carbon dioxide, nitric oxide,water, phenol, methanol, ethanol, absolute alcohol, isopropanol,propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid,lactic acid, propyl iodide, isopropyl, iodide, ethyl iodide, methylacetate, ethyl acetate, ethyl nitrate, isopropyl acetate, and ethyllactate, and mixtures thereof.

Embodiment 29 provides the method according to any one of Embodiments1-28, wherein the formulation comprises a therapeutic agent for nervedenervation, wherein the therapeutic agent is chosen from sodium channelMockers, tetrodotoxins, saxitoxins, decarbamoyl saxitoxins,neosaxitoxins, lidocaines, conotoxins, cardiac glycosides, digoxins,glutamates, staurosporines, amlodipines, verapamils, cymarins,digitoxins, proscillaridins, quabains, veratridines, domoic acids,oleandrins, carbamazepines, aflatoxins, guanethidines, and guanethidinesulfates.

Embodiment 30 provides the method according to any one of Embodiments1-29, wherein the formulation comprises a contrast agent for imagingnerve denervation, wherein the contrast agent is chosen from iodine,ethyl iodide, sodium iodide, lipiodol, nonoxynol iodine, iobitridol,iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversal, ioxilan,iotrolan, iodixanol, or ioxaglate, and derivatives thereof.

Embodiment 31 provides the method according to any one of Embodiments1-30, wherein the formulation comprises an azeotrope.

Embodiment 32 provides the method according to Embodiment 31, whereinthe azeotrope is chosen from ethanol/water, propanol/water,isopropanol/water, butanol/water, acetic acid/water, lactic acid/water,ethyl lactate/water, ethyl lactate/ethanol, lactic acid/ethanol/water,ethyl lactate/water/ethanol, ethyl acetate/ethanol, ethylnitrate/ethanol, and isopropyl acetate/ethanol.

Embodiment 33 provides the method according to any one of Embodiments1-32, wherein the formulation comprises one of ethanol, ethanol/water,ethanol/water/oxygen, ethanol/water/air, ethanol/water/contrast agent,ethanol/water/surfactant, ethanol/water/contrast agent/surfactant,propanol/water, isopropanol/water, butanol/water, and/or aceticacid/water.

Embodiment 34 provides a dilating balloon catheter for delivery of aformulation to a target location in a body lumen of a patient, thedilating balloon catheter comprising a proximal end, a distal end, awire lumen, a balloon inflation lumen, a formulation infusion lumenand/or a vacuum lumen, an expandable balloon and a non-expandable shaft,wherein the expandable balloon section and/or the non-expandable shaftcomprises at least a first section having a plurality of voids, whereinthe voids are micro-holes, and wherein the expandable balloon sectionand/or the non-expandable shaft comprises at least a second sectionhaving no voids.

Embodiment 35 provides the dilating balloon catheter of Embodiment 34,wherein the expandable section has a first distal, a first middle and afirst proximal section, wherein the diameter of the first distal sectionand the first proximal section are larger than the diameter of the firstmiddle section.

Embodiment 36 provides the dilating balloon catheter of any one ofEmbodiments 34-35, wherein the expandable section or non-expandablesection has at least one void that allows the formulation to penetrateinto the wall of the body lumen at a pressure higher than that of thebody lumen; and wherein the expandable section or non-expandable sectionhas no void that allows the balloon to dilate the body lumen at apressure higher than that of the body lumen.

Embodiment 37 provides the dilating balloon catheter of any one ofEmbodiments 34-36, wherein the body lumen is chosen from a renal artery,a pulmonary artery, avuncular lumen, a celiac artery, a common hepaticartery, and a proper hepatic artery, a gastroduodenal artery, arighthepatic artery, a left hepatic artery, a splenic artery, a right gastricartery, a left gastric artery, a nonvascular lumen, an airway, a sinus,an esophagus, a respiratory lumen, a digestive lumen, a stomach, aduodenum, a jejunum, a prostate, a urethra, a ureter, and a urologicallumen.

Embodiment 38 provides the dilating balloon catheter of any one ofEmbodiments 34-37, wherein the formulation is at a pressure ranging from0.1 atm to 14 atm during delivery, and the dilated balloon catheter isinflated at a pressure ranging from 0.1 atm to 14 atm.

Embodiment 39 provides the method according to any one of Embodiments1-38, further comprising flushing the body lumen with saline solution todilute the formulation.

Embodiment 40 provides the method according to any one of Embodiments1-39, wherein the removing of the formulation from the body lumen isperformed.

Embodiment 41 provides the method or balloon catheter of any one or anycombination of Embodiments 1-40 optionally configured such that allelements or options recited are available to use or select from.

1-40. (canceled)
 41. A method for treating a disease, the methodcomprising: a) inserting a delivery catheter into a body lumen; b)infusing a formulation into a diseased tissue in the body lumen, whereinan amount of the formulation delivered to the body lumen is effective toinjure or damage the diseased tissue to relieve disease symptoms; c)optionally removing the formulation from the body lumen; and d)withdrawing the delivery catheter from the body lumen.
 42. The methodaccording to claim 41, wherein the disease is chosen from hypertension,pulmonary hypertension, diabetes, obesity, heart failure, end-stagerenal disease, a digestive disease, nonalcoholic fatty liver disease,benign prostate hyperplasia, cancers, tumors, pain, asthma and chronicobstructive pulmonary disease (COPD).
 43. The method according to claim41, wherein the body lumen is chosen from a renal artery, a pulmonaryartery, a vascular lumen, a celiac artery, a common hepatic artery, aproper hepatic artery, a gastroduodenal artery, a right hepatic artery,a left hepatic artery, a splenic artery, a right gastric artery, a leftgastric artery, a nonvascular lumen, an airway, a sinus, an esophagus, arespiratory lumen, a digestive lumen, a stomach, a duodenum, a jejunum,a prostate, a urethra, a ureter, and/or a urological lumen.
 44. Themethod according to claim 41, wherein the formulation consists ofethanol.
 45. The method according to claim 41, wherein the formulationis at a temperature ranging from −40° C. to 150° C.
 46. The methodaccording to claim 41, wherein pressure of the formulation duringinfusion ranges from 0.1 atm to 14 atm.
 47. The method according toclaim 41, wherein an amount of the formulation infused into the diseasedtissue ranges from 0.2 microliters to 200 milliliters.
 48. The methodaccording to claim 41, wherein the method comprises inserting thedelivery catheter into the body lumen for about 2 seconds to about 60minutes.
 49. The method according to claim 41, wherein the methoddelivers an amount of heat or energy ranging from about 2 cal/g to about150 cal/g to the diseased tissue.
 50. The method according to claim 41,wherein the delivery catheter is chosen from a needle or needle-baseddelivery catheter, a single balloon delivery catheter, a double balloondelivery catheter, an infusion catheter, a balloon infusion catheter, aballoon catheter, a dumbbell balloon infusion catheter, and combinationsthereof.
 51. The method according to claim 50, wherein the deliverycatheter is inflated at a pressure ranging from 0.1 atm to 14 atm. 52.The method according to claim 41, wherein the formulation comprises oneor more ingredients chosen from water, saline, hypertonic saline,phenol, methanol, ethanol, absolute alcohol, isopropanol, propanol,butanol, isobutanol, ethylene glycol, glycerol, acetic acid, lacticacid, propyl iodide, isopropyl iodide, ethyl iodide, methyl acetate,ethyl acetate, ethyl nitrate, isopropyl acetate, ethyl lactate,lipiodol, urea, and derivatives and combinations thereof.
 53. The methodaccording to claim 41, wherein the formulation comprises a gas or vaporchosen from oxygen, nitrogen, helium, argon, air, carbon dioxide, nitricoxide, water, phenol, methanol, ethanol, absolute alcohol, isopropanol,propanol, butanol, isobutanol, ethylene glycol, glycerol, acetic acid,lactic acid, propyl iodide, isopropyl, iodide, ethyl iodide, methylacetate, ethyl acetate, ethyl nitrate, isopropyl acetate, and ethyllactate, and mixtures thereof.
 54. The method according to claim 41,wherein the formulation comprises a therapeutic agent for nervedenervation, wherein the therapeutic agent is chosen from sodium channelblockers, tetrodotoxins, saxitoxins, decarbamoyl saxitoxins, vanilloids,neosaxitoxins, lidocaines, conotoxins, cardiac glycosides, digoxins,glutamates, staurosporines, amlodipines, verapamils, cymarins,digitoxins, proscillaridins, quabains, veratridines, domoic acids,oleandrins, carbamazepines, aflatoxins, guanethidines, and guanethidinesulfates.
 55. The method according to claim 41, wherein the formulationcomprises a contrast agent for imaging nerve denervation, wherein thecontrast agent is chosen from iodine, ethyl iodide, sodium iodide,lipiodol, nonoxynol iodine, iobitridol, iohexol, iomeprol, iopamidol,iopentol, iopromide, ioversal, ioxilan, iotrolan, iodixanol, orioxaglate, and derivatives thereof.
 56. The method according to claim41, wherein the removing of the formulation from the body lumen isperformed.
 57. The method according to claim 41, further comprisingflushing the body lumen with saline solution to dilute the formulation.58. A dilating balloon catheter for delivery of a formulation to atarget location in a body lumen of a patient, the dilating ballooncatheter comprising a proximal end, a distal end, a wire lumen, aballoon inflation lumen, a formulation infusion lumen and/or a vacuumlumen, an expandable balloon and a non-expandable shaft, wherein theexpandable balloon section and/or the non-expandable shaft comprises atleast a first section having a plurality of voids, wherein the voids aremicro-holes, and wherein the expandable balloon section and/or thenon-expandable shaft comprises at least a second section having novoids.
 59. The dilating balloon catheter of claim 58, wherein theexpandable section has a first distal, a first middle and a firstproximal section, wherein the diameter of the first distal section andthe first proximal section are larger than the diameter of the firstmiddle section.
 60. The dilating balloon catheter of claim 58, whereinthe expandable section or non-expandable section has at least one voidthat allows the formulation to penetrate into the wall of the body lumenat a pressure higher than that of the body lumen; and wherein theexpandable section or non-expandable section has no void that allows theballoon to dilate the body lumen at a pressure higher than that of thebody lumen.